FRONTIERS IN ENDOSCOPY, SERIES #62

Low Lying Rectal Stents: How Low Can You Go?

May 2020 • Volume XLIV, Issue 5
Kathryn Schmidt,Douglas G. Adler

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INTRODUCTION

In patients with low lying rectal obstruction due to malignancy, there is ongoing debate regarding whether self-expanding metallic stent (SEMS) placement within 5 cm of the anal verge is a feasible, efficacious alternative to surgery.1-5 Very few randomized control trials have included patients with low lying malignant rectal obstructions. Much hesitation exists in stenting close to the anal verge or the dentate (pectinate) line, which is the anorectal junction and is about 2 cm from the anal verge. Regardless of the etiology of the obstruction, rectal stenting may be indicated for symptomatic relief in non-surgical candidates or high-risk patients, or as a bridge to surgery, allowing for optimization of the patients’ health prior to the surgical intervention.6,7 (Figure 1) While SEMS placement within 5 cm of the anal verge has been approached in a guarded manner due to fears of high rates of adverse effects including proctalgia, tenesmus, incontinence, mucosal ulceration, bleeding, stent migration, and perforation, among other complications, there are multiple factors to consider in determining whether this is a safe and feasible option. In addition to a comprehensive risk-benefit analysis, the type of stent, the method of stent placement, the addition of chemotherapy or radiation, the endoscopists’ experience in placing stents, and the patients’ etiology and location of obstruction should be considered.1-7 (Figure 2)

Since its introduction in the 1990 s, SEMS placement for acute malignant colorectal obstruction has become a widely adopted alternative to surgery. SEMS placement is considered a safe and feasible alternative to emergent surgery for decompression of colorectal obstruction, either for palliation in poor surgical candidates or as a bridge to surgery.8,9 In poor surgical candidates, SEMS relieves obstructive symptoms, improving patients’ quality of life. In patients with surgically incurable colorectal cancer, patients who received stents had improved morbidity and mortality compared to patients who underwent surgery.10 As a bridge to surgery, temporary stent placement allows for elective rather than emergent surgery, which is associated with lower short-term morbidity and lower rates of temporary and permanent stomas.11,12

Less data exists regarding the feasibility and efficacy of stent placement in colorectal obstructions that are within 5 cm of the anal verge. Historically, SEMS placement in these low-lying colorectal obstructions has been approached in a guarded manner due to fears of adverse effects including proctalgia, tenesmus, incontinence, mucosal ulceration, bleeding, stent migration, and perforation.9,13 In recent years, there has been increasing data to suggest that stent placement within 5 cm of the anal verge is both safe and clinically effective as a treatment modality for low-lying colorectal obstruction, although many practitioners are still hesitant to place a low lying rectal stent.13 This review will discuss the indications, techniques, and outcomes of colonic stenting in the distal rectum.

Risk Factors Influencing Clinical Failure

Malignant colorectal obstruction may be caused by primary colorectal cancer or an extracolonic malignancy (i.e. urogenital, gynecologic, gastric, or pancreaticobiliary).14,15 Clinical outcomes of SEMS placement for colorectal obstruction due to an extracolonic malignancy tend to be less favorable. Extrinsic compression causing colonic obstruction is reported to be a major cause of technical failure in colorectal SEMS placement.16 However, technical and clinical success rates of SEMS placement in this scenario varies widely across studies.17,18 Data also suggests that stent patency is lower when the etiology of the obstruction is due to extracolonic malignancy rather than primary colorectal cancer.3 Considering the etiology of malignancy is important, specifically in the case of lower rectal obstructions, because data has shown that obstruction attributed to extracolonic malignancy, not rectal obstruction itself, is an independent risk factor for clinical failure and complications (by both univariate and multivariate analysis in a study by Lee et al.).15

Carcinomatosis also appears to be a risk factor influencing clinical failure (by univariate analysis in a study by Lee et al.) regardless of if the stent is placed for a lower rectal obstruction.15 This may be due to the differences in peritoneal infiltration patterns and in the severity of peritoneal carcinomatosis between patients with extracolonic malignancy and primary colorectal cancer.19 This may have clinical implications for patient selection with regard to stenting for lower rectal obstructions.

Risks of Stenting ≤5 cm From Anal Verge: Anal Pain

A phase 2 clinical study was conducted, during which 33 patients with non-resectable obstruction of the rectum or sigmoid colon had an uncovered metal stent placed through the anus in an obstructive portion under x-ray fluoroscopic guidance. While anal pain occurred in 5 patients, only 1 patient required stent removal due to intolerable pain.20 Song et al. reported that 10 out of 16 (62.5%) patients with stents placed for obstruction within 5 cm (range 25-50mm) of the anal verge complained of anal pain. In 3 of these patients, the pain resolved within 7 days or was tolerated without analgesics. The remaining 7 patients tolerated the pain with analgesics. In all cases, the stent was deployed in a manner by which the distal tip of the stent was located at least 5 mm proximal to the dentate line. This was in comparison to 14 patients with stents placed greater than 5 cm from the anal verge, 1 (7.1%) of whom complained of anal pain. In this study, stent migration occurred in 4 patients, all of whom experienced intolerable pain despite analgesics, likely due to irritation and sensory innervation to the anal canal by the unfixed distal end of the migrated stent as it moved beyond the dentate line. This study suggests that stents placed 5 mm proximal to the dentate line, but not within the anal canal, are usually tolerable to patients from a pain perspective. It also highlights the importance of accurately measuring the distance from the distal end of the obstruction to the dentate line.9

Lee et al. described a novel method for SEMS placement with a proximal-release delivery system (PRDS) to allow for precise SEMS placement for malignant rectal obstruction within 5 cm of the anal verge. The stent is released under endoscopic and fluoroscopic guidance. It is released by pushing the cover sheath, and the proximal portion is expanded before the distal, which differs from conventional stents. In this study, 2 out of 6 patients reported anal pain, tolerable with analgesics in both cases and which resolved within days. Additionally, no patients reported defecation difficulty, incontinence, or foreign body sensation.21

In another study by Lee et al., anal pain occurred more often in patients with stents successfully placed for lower rectal obstruction (<5 cm from anal verge) than upper rectal or left colonic obstruction (14.8% vs 6.2% vs 0.3%; p < 0.001), but ultimately, only a small number (4/27, 14.8%) of patients with lower rectal obstruction reported anal pain. Pain was well controlled by analgesics in 1 patient, but intolerable in the other 3. In 1 patient, this was due to stent migration. The remaining 2 patients’ pain was resolved with either surgery or radiotherapy. In this study, stents were successfully placed in patients as close as 10 mm from the anal verge (range of 10-50 mm from the anal verge). The authors concluded that appropriately positioning the distal end of a SEMS via fluoroscopy-assisted endoscopy is crucial in stenting ≤5 cm from the anal verge.15

Other studies also suggest that pain is more common in patients with stent placement in the rectum. In a study with placement of a dual stent using a 4.5-mm stent delivery system, 5 of the 34 patients who received rectal stents experienced severe rectal pain 2 – 22 hours after stent placement that required analgesics. None of the other 111 patients in the study who had stents placed in other parts of the colon complained of pain.22 In another study with dual stent design, Kim et al. aimed to compare the clinical safety and efficacy of dualdesign expandable colorectal stents with flared and bent ends in the treatment of patients with malignant colorectal obstruction. Four of the 35 patients (2 in each group) with stents placed in the rectum complained of rectal pain 2-15 hours after stent placement, while none of the 81 patients with stents placed elsewhere in the colon reported pain. The pain was mild and successfully managed with analgesics.23

Tenesmus

Tenesmus is a known complication of rectal stenting.5,15,21 (Figure 3) In a study by Bayraktar et al., authors retrospectively analyzed data from 49 patients with colorectal cancer who had undergone stent placement. Eighteen of these patients had obstruction in the rectum. Overall, tenesmus occurred in 8.1% of patients. This complication was more common in patients who were stented for rectal obstruction (25%) than proximal tumors. Tenesmus was defined as both an early (<7 days) and late (>7 days) complication after stent placement in patients with obstructive rectal cancer.24 Ultimately, to reduce the risk of tenesmus in patients with rectal obstructions within 5 cm of the anal verge, the distal portion of the stent should be placed as proximally as is technically feasible to relieve the obstruction.21

Bleeding

Bleeding is typically a minor complication of colorectal stent placement; significant hemorrhage following stenting is rare.25,26 Bleeding secondary to stent placement generally does not require intervention and can often be managed conservatively.9,27 In a study by Lee et al., 136 of 482 successfully stented patients experienced complications. Bleeding was the fourth most common complication (n = 13; 2.7%), after reobstruction (n = 103; 21.4%), stent migration (n = 22; 4.6%), and perforation (n = 17; 3.5%).15 It should be noted that the rates of complications in this study, especially the rate of perforation, are exceptionally high when compared to other studies, and the reasons for this remain unclear. In a phase 2 clinical study, bleeding only occurred in 1 of 33 patients with stent placement for unresectable obstruction of the rectum or sigmoid colon.20 In a prospective study investigating the technical feasibility, clinical effectiveness, and safety of a dual-design colorectal stent (consisting of an outer stent and an inner bare nitinol stent) in patients with malignant colorectal obstruction, bleeding occurred in 2 patients in the bridge-tosurgery group (n = 50) and in 6 patients in the palliative group (n = 101). In all cases, bleeding resolved spontaneously. This study included 34 patients with obstruction specific to the rectum, but it is unclear if patients with rectal obstruction experienced more significant bleeding than patients with obstruction in the rectosigmoid junction (n = 35), sigmoid colon (n = 56), descending colon (n = 10), or transverse colon (n = 16).

This study utilized a dual stent design, which was designed to take advantage of the strengths of both bare and covered stents. The inner and outer stents were each loaded via their own delivery systems. The inner stent was 2 cm shorter than the outer stent, which consisted of three parts: a proximal bare nitinol stent, a nylon mesh, and a distal bare nitinol stent. Both ends of the stent were flared up to 38 mm. The dual stent is believed to be superior to conventional stents in the treatment of colorectal obstruction in two ways: lower risk of stent migration and no tumor ingrowth, resulting in less recurrent obstruction. However, the dual design stent in this particular study also had disadvantages including a more complicated delivery system and risk for perforation due to the diameter of the flared ends of the inner bare stent, which authors investigated further in a followup study.22 In a study that compared the clinical safety and efficacy of dual-design expandable colorectal stents with flared ends with those of stents with bent ends in the treatment of patients with malignant colorectal obstruction, bleeding occurred after stent placement in 1 patient with a flared-end stent and 3 patients with bent-end stents. Bleeding resolved spontaneously in all cases.23

In another prospective clinical cohort study, 447 patients with malignant large-bowel obstruction (15.8% of tumors were specific to the rectum) received colorectal through-the-scope SEMS placement. Only 2 (0.5%) cases of bleeding were identified. Bleeding occurred in 0.4% (2/447) of patients within 6 hours of stent placement and in 0.5% (2/382) of patients within 30 days (cumulatively). The bleeding appeared to be a procedural complication due to stent placement rather than rectal in origin. The denominator of 382 patients with a 30-day follow-up visit reflects discontinuation of follow-up before 30 days due to safety events.27

Incontinence

Fecal incontinence can occur with stents placed distally in the rectum, particularly if the distal end of the stent is within 2 cm proximal to the upper end of the anal canal.28 Some patients have also described a constant urge to defecate or a foreign body sensation, sometimes referred to as tenesmus.5 In a study conducted to investigate the clinical outcomes of SEMS in malignant rectal obstruction in comparison with those in left colonic obstruction, Lee et al. found incontinence to be rare. It occurred at a lesser rate (n = 1; 0.2%) than other complications including reobstruction (n = 103; 21.4%), stent migration (n = 22; 4.6%), perforation (n = 17; 3.5%), bleeding (n = 13; 2.7%), and anal pain (n = 11; 2.2%). However, the complication rate was overall higher in patients with rectal obstruction (37.4% vs 25.1%; p = 0.01).15

In another study by Lee et al., authors utilized a novel approach – the PRDS, as described previously – to place stents in 6 patients with symptomatic malignant lower rectal obstruction with lesions located within 5 cm of anal verge (5 patients with rectal cancer, 1 with bladder cancer). The palliative PRDS differs from conventional stents in that the proximal portion is expanded before the distal. The authors evaluated fecal incontinence and defecation issues as an outcome measure; no patients in this study experienced any incontinence or defecation issue including foreign body sensation.21

Reobstruction/Stent Occlusion

Stent occlusion can occur due to tumor ingrowth or outgrowth or, rarely, by stool impaction.2,3 In a retrospective study of 55 patients who underwent placement of an uncovered SEMS for palliative treatment of malignant colorectal obstruction with metastatic or locally advanced, surgically unresectable cancer, stent occlusion caused by tumor ingrowth or overgrowth (n = 8) was the most common complication (15.4%). Stent occlusion occurred at a mean time of 127 days between stent placement and occlusion (range, 31–360 days). The single patient with tumor overgrowth was treated with placement of an additional stent at the proximal end of the stent. Six patients with tumor ingrowth were treated by overlapping the occluded stent with a second stent. Study authors used the Cox proportional hazard model to identify predictive factors associated with stent occlusion and found that insufficient stent expansion (<70%) 48 hours status post stent placement was significantly associated with increased risk of stent occlusion (odds ratio, 12.55; 95% CI, 2.52–62.48; p = 0.002). The likelihood of stent occlusion by tumor growth increases with the time elapsed after stent placement. Of key importance, in this particular study, the site of obstruction was mainly in the sigmoid colon and rectum (69.1%); while stent placement occurred most commonly in the rectum (23 patients, 41.8%), the authors did not delineate complications by site of obstruction.29 In a prospective study, stent occlusion occurred in 5 of 151 patients (rectal obstruction = 38) with a dual-design colorectal stent (outer stent and an inner bare nitinol stent) following placement for colorectal cancer (n = 115), gastric cancer (n = 25), cervical cancer (n = 3), pancreatic cancer (n = 2), ovarian cancer (n = 2), gallbladder cancer (n = 1), cholangiocarcinoma (n = 1), urinary bladder cancer (n = 1), and renal transitional-cell cancer (n = 1). Stent occlusion was caused by tumor overgrowth in all five cases. These patients were successfully treated by placement of a second (coaxial) stent into the first stent with overlap at the ends.22

Stent Migration

Stent migration represents one of the most common complications (overall incidence 10–11%, up to 50% of patients in some studies) after SEMS placement for colorectal obstruction. Notably, stent placement in the distal rectum is cited as one of the predisposing factors for stent migration. Stent migration may be asymptomatic or symptomatic, with the latter type generally requiring endoscopic repositioning, removal or replacement. In rare cases, migration may lead to additional complications such as recurrent obstruction or perforation.30-32 In a retrospective study at a tertiary referral university hospital, Song et al. investigated the technical feasibility, clinical effectiveness, and safety of expandable metallic stent placement in patients with malignant rectal obstruction within 5 cm of the anal verge. Sixteen patients had rectal obstructions within 5 cm (range, 25-50 mm) of the anal verge (Group A) and 14 patients had rectal obstructions > 5 cm (range, 53-74 mm) from the anal verge (Group B). Stent migration occurred in 1 patient in group A and in 3 patients in group B. All four stents were removed due to intolerable anal pain, despite analgesic use, secondary to stent migration.9

In another retrospective study, the authors aimed to investigate the clinical outcomes of SEMS in malignant rectal obstruction in comparison to left colonic obstruction. Of 573 patients enrolled in the study, 154 (26.9%) underwent SEMS placement for rectal obstruction. In 39/154 patients, rectal obstruction was located ≤5 cm from the anal verge. Stent migration was the second most common complication in this study (n = 22; 4.6%). Four patients with rectal obstruction experienced early and late stent migration, 2 of whom had obstructions <5 cm from the anal verge. In one of these cases, the patient had received a covered stent for obstruction located 4 cm from the anal verge; stent migration caused pain, requiring removal and reinsertion. In the second case, the tumor was located 5 cm from the anal verge and the patient received an uncovered SEMS-this patient ultimately underwent curative surgery. In the left colonic obstruction group, 4 and 10 patients experienced early and late stent migration, respectively.15

The overall complication rate was higher in patients with rectal obstruction (37.4% vs 25.1%; p = 0.01). However, most of the complications in patients with rectal obstruction were managed successfully with endoscopic treatment (41.3%). In this study, the majority of the patients (77.1%) received uncovered stents, which differs from the previously mentioned study by Song et al.15

Yet another retrospective analysis was performed with 55 patients who underwent placement of uncovered SEMS for palliative treatment of malignant colorectal obstruction. The obstruction site was located in the rectum in 23 patients (41.8%). Stent migration was the second most common complication (10.9%, 6/55). Early stent migration (<1 week after stent placement) developed in 5 patients, 2 of whom had partial distal migration and received additional stent insertion and 3 of whom had complete migration in which the stent was expelled out of the anus. Two of the latter patients required no further intervention and the other patient underwent stent reinsertion. Late stent migration (≥1 week after stent placement) developed in only 1 patient with sigmoid colon cancer and in no patients with rectal obstruction.30 In a prospective study of a dual-design colorectal stent (consisting of an outer stent and an inner bare nitinol stent) placement was performed in 151 patients with malignant colorectal obstruction. Stent migration did not occur in the bridge-tosurgery group, but occurred in 4 patients in the palliative group, 1 of whom had obstruction specific to the rectum.22

Perforation

Perforation is a rare but serious complication of colorectal stent placement, often related to the tortuosity of the rectosigmoid junction, insertion technique, or the endoscopists’ experience.3,7,23,33 Other risk factors include balloon predilation, excessive manipulation of stent wires, laser recanalization prior to SEMS placement (which is rarely performed in the current era), and possibly related to concomitant bevacizumab use, an angiogeneic inhibitor.3 However, a recent study by Lee et al. suggests that bevacizumab may no longer be a risk factor for perforation.34 Perforation typically requires surgical intervention.3

While these are commonly cited risk factors, in one study, the authors conducted a multivariate logistic analysis with forward stepwise selection and found that complete obstruction was the only significant independent factor for perforation (odds ratio 6.88, 95 % CI 2.04 – 23.17, P = 0.002); age, sex, site and length of the obstruction, the source of the malignancy, and balloon dilation before and after stent placement were not related to the likelihood of perforation.22 Stent placement due to obstruction in the lower rectum does not appear to increase the risk for perforation.

In a different prospective study, 49 patients underwent uncovered SEMS placement for malignant colorectal obstruction, 15 (30.6%), of whom had rectal obstruction. Perforation occurred in 1 patient with rectal cancer 87 days after SEMS placement proximal to the stent placement site, which required a Hartmann’s operation. It is unclear how low in the rectum the stent was placed. For comparison, the only other perforation in this study occurred immediately after stent deployment in a patient with a sigmoid colonic obstruction, and the patient received emergent palliative left hemi-colectomy.35

In a retrospective study at a tertiary hospital, Song et al. investigated the technical feasibility, clinical effectiveness, and safety of SEMS in patients with malignant rectal obstruction within 5 cm of the anal verge. Sixteen patients had rectal obstructions within 5 cm (range, 25-50 mm) of the anal verge (Group A) and 14 patients had rectal obstructions > 5 cm (range, 53-74 mm) from the anal verge (Group B). The perforation rate was 6.7% (2/30). Colonic perforation occurred in 8% (2/25) of patients with dual stents at 10 and 50 days after stent placement. In one case, perforation was related to the stent wiring, and the site of perforation could not be detected. In the other patient, the perforation occurred in the colon, proximal to the tumor bed, due to pressure necrosis from flared ends of the inner bare stent of the dual stent. In one patient, the length between the lower margin of obstruction and the anal verge before stent placement was 50 mm. The length between the lower margin of the placed stent and the anal verge 1 to 3 days after stent placement was 25 mm. In the other patient, the length between the lower margin of obstruction and the anal verge before stent placement was 70 mm. The length between the lower margin of the placed stent and the anal verge 1 to 3 days after stent placement was 40 mm. Both patients required emergent colostomy. No perforations occurred in patients with fully covered retrievable stents. The authors concluded that stent placement is safe in the lower rectum and that the diameter of flared ends of dual stents should be reduced to decrease risk for perforation.9

In a study comparing the clinical safety and efficacy of dual-design expandable colorectal stents with flared (n = 69) or bent (n = 53) ends in the treatment of 122 patients with malignant colorectal obstruction, perforation occurred nine days after stent placement with flared ends in 1 patient with rectal obstruction. The exact site of perforation in the rectum was unknown. Seven cases of colonic perforation (6%) occurred, but authors did not find significant differences between the rates of colonic perforation in the two groups and the overall complication rates were similar (p > 0.05).23

In another retrospective study, authors investigated the clinical outcomes of SEMS in malignant rectal obstruction in comparison to left colonic obstruction. Of 573 enrolled patients, 154 (26.9%) underwent SEMS placement for rectal obstruction. In 39/154 patients, rectal obstruction was located ≤5 cm from the anal verge. Perforation occurred in 1 patient with upper rectal obstruction, but did not occur in any patients with lower rectal obstruction.15

Lumen Apposing Metal Stents (LAMS)

Initially designed for the drainage of pancreatic fluid collections, the Axios stent (Boston Scientific, Natick MA) is a 1cm long, fully covered LAMS available in 10, 15, and 20mm dm in the United States. Axios stents may be beneficial to patients with complex, severe, and refractory stenosis located within 5 cm of the anal verge.

Many reports of Axios stents being used to treat luminal obstruction in the large bowel exist. There are a few reports of the use of the Axios stent in an off-label manner to treat low-lying rectal obstruction. In one report, a 49 year old male with sigmoid adenocarcinoma developed severe, filiform, eccentric stenosis 5 cm from the anus that could not be resolved by traditional endoscopic dilation. After successive dilations failed (using a through-the-scope, over-the-wire balloon under fluoroscopic guidance), a 15mm wide Axios stent was placed across the stricture under endoscopic and radiologic guidance. The patient tolerated the stent without further complication and with adequate intestinal transit at his two month followup.1

In another case report, a 66 year old male, who underwent a low anterior resection with loop ileostomy for colorectal malignancy, developed complete obstruction of the rectal anastomosis. Recanalization of the lumen was successfully performed with a 15mm wide Axios stent. While this stent was designed for transenteric drainage, in this case, it functioned to maintain patency after total rectal anastomotic stenosis.36

Risk-Benefit Analysis

While the risk for certain adverse effects may be increased when stenting in the case of lowlying rectal obstruction, complications are rare and can often be managed through endoscopic intervention including stent reinsertion, balloon dilatation, and hemostasis.15 Argon plasma coagulation (APC) has also been utilized when complications arise after stent placement for rectal obstruction. It may be used to trim malpositioned or migrated endoscopic SEMS. Molina-Infante et al. described a case of APC endoscopic transection of an embedded segment from a distally migrated, uncovered rectal stent, complicated by ulcerations due to impaction against the rectal wall after failed removal via endoscopic en bloc due to diffuse tumoral ingrowth.37 In another case, APC was used successfully to trim a stent in an 86-year-old female with obstructing rectal cancer who underwent placement of a colonic SEMS with a portion of free flange in the distal rectum.38

Anal pain, a feared complication with stent placement so close to the anal verge, is tolerable to most patients with or without analgesics, although patients may choose to undergo palliative radiotherapy to reduce pain, which is also experienced by patients whose tumors are >5 cm from the anal verge.15 Tumor ingrowth can be managed with APC, ablation of the obstruction, or (most commonly) via placement of a second stent while tumor overgrowth can be managed with an additional stent.2,3 Perforations, while rare, can occur and often require surgery. In some instances, conservative medical therapy may be utilized including nasogastric tube insertion, antibiotics, and total parenteral nutrition while allowing perforations to spontaneously resolve.3

Stent placement in patients with obstructions <5 cm from the anal verge allows patients to avoid surgical intervention and colostomy/stoma while maintaining continence and with minimal adverse impact on quality of life.3-5, 33 Stent placement is also more cost-effective than stoma creation for patients with inoperable malignant colonic obstructions and results in shorter hospital stay.5

CONCLUSION

Can we stent within 5 cm of the anal verge? Yes. Stenting within 5 cm of the anal verge is possible and should be considered in certain patients. Complications may not occur as often as what was once thought and can often be resolved without additional adverse events. Ultimately, patients may avoid colostomy or invasive surgical procedures and have improved quality of life. In conclusion, stent placement within 5 cm of the anal verge is safe, feasible, and efficacious, and a reasonable alternative to surgery as palliative care or as a bridge to surgery in carefully selected patients.

References

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21. Lee KM, Lim SG, Shin SJ, Kim JH, Kang DH, Kim JK, Hwang JC, Kwon CI, Cheong JY, Yoo BM. Novel method of stent insertion for malignant lower rectal obstruction with proximal releasing delivery system (with video). Gastrointest Endosc. 2013 Dec;78(6):930-933. doi: 10.1016/j.gie.2013.08.018. PubMed [citation] PMID:24237948

22. H.Y. Song, J.H. Kim, J.H. Shin, et al.A dual-design expandable colorectal stent for malignant colorectal obstruction: results of a multicenter study. Endoscopy, 39 (2007), pp. 448-454

23. Kim JH, Song HY, Li YD, Shin JH, Park JH, Yu CS, Kim JC. Dual-design expandable colorectal stent for malignant colorectal obstruction: comparison of flared ends and bent ends. AJR Am J Roentgenol. 2009 Jul;193(1):248-54. doi: 10.2214/AJR.08.2003. PubMed [citation] PMID: 19542421

24. Bayraktar B, Ozemir IA, Kefeli U, et al. Colorectal stenting for palliation and as a bridge to surgery: A 5-year follow-up study. World J Gastroenterol. 2015 Aug 21; 21(31): 9373-9.

25. Small AJ, Coelho-Prabhu N, Baron TH. Endoscopic placement of self-expandable metal stents for malignant colonic obstruction: long-term outcomes and complication factors. Gastrointest Endosc. 2010;71:560–572.

26. Park JH, Oh SH, Lee WY, Choo SW, Do YS, Chun HK. Flexible rectal stent for obstructing colonic neoplasms. J Korean Soc Coloproctol. 2000;16:267–273.

27. Meisner S, González-Huix F, Vandervoort JG, Goldberg P, Casellas JA, Roncero O, Grund KE, Alvarez A, García-Cano J, Vázquez-Astray E, Jiménez-Pérez J; WallFlex Colonic Registry Group.. Self-expandable metal stents for relieving malignant colorectal obstruction: short-term safety and efficacy within 30 days of stent procedure in 447 patients. Gastrointest Endosc. 2011 Oct;74(4):876-84. doi: 10.1016/j.gie.2011.06.019. PubMed [citation] PMID: 21855868

28. Baron TH. Colonic stenting: technique, technology, and outcomes for malignant and benign disease. Gastrointest Endosc Clin N Am. 2005;15:757–771.

29. Suh JP, Kim SW, Cho YK, et al. Effectiveness of stent placement for palliative treatment in malignant colorectal obstruction and predictive factors for stent occlusion. Surg Endosc. 2010;24:400– 406. doi: 10.1007/s00464-009-0589-x.

30. Bielawska B, Hookey LC, Jalink D. Large-diameter self-expanding metal stents appear to be safe and effective for malignant colonic obstruction with and without concurrent use of chemotherapy. Surg Endosc. 2010;24:2814–2821. doi: 10.1007/s00464010-1055-5.

31. de Gregorio MA, Laborda A, Tejero E, et al. Ten-year retrospective study of treatment of malignant colonic obstructions with self-expandable stents. J Vasc Interv Radiol. 2011;22:870–878. doi: 10.1016/j.jvir.2011.02.002.

32. Saida Y, Enomoto T, Takabayashi K, Otsuji A, Nakamura Y, Nagao J, Kusachi S. Outcome of 141 cases of self-expandable metallic stent placements for malignant and benign colorectal strictures in a single center. Surg Endosc. 2011 Jun;25(6):1748-52. doi: 10.1007/ s00464-010-1310-9. Epub 2011 Mar 25. PubMed [citation] PMID: 21437740

33. Vu TM, Simpson JA, Alzarhani S, Lynch AC, Warrier S, Heriot A. Rectal adenocarcinoma perforation following palliative colorectal stenting. ANZ J Surg. 2018 Jun;88(6):E558-E559. doi: 10.1111/ ans.13480. Epub 2016 Dec 18. No abstract available. PubMed [citation] PMID: 27990786

34. Lee JH, Emelogu I, Kukreja K, Ali FS, Nogueras-Gonzalez G, Lum P, Coronel E, Ross W, Raju GS, Lynch P, Thirumurthi S, Stroehlein J, Wang Y, You YN, Weston B. Safety and efficacy of metal stents for malignant colonic obstruction in patients treated with bevacizumab. Gastrointest Endosc. 2019 Jul;90(1):116-124. doi: 10.1016/j.gie.2019.02.016. Epub 2019 Feb 21. PubMed [citation] PMID: 30797835

35. Im JP, Kim SG, Kang HW, Kim JS, Jung HC, Song IS. Clinical outcomes and patency of self-expanding metal stents in patients with malignant colorectal obstruction: a prospective single center study. Int J Colorectal Dis. 2008 Aug;23(8):789-94.doi: 10.1007/s00384-008-0477-1. Epub 2008 Apr 29. PubMed [citation] PMID:18443807

36. 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 Oct;82(4):752. doi: 10.1016/j.gie.2015.05.003. Epub 2015 Jun 10. No abstract available. PubMed [citation] PMID: 26071063

37. Molina-Infante J, Mateos-Rodriguez JM, Fernandez-Bermejo M, Perez-Gallardo B,Hernandez-Alonso M. Endoscopic trimming of an embedded distally migrated metallic rectal stent with argon plasma coagulation. Surg Laparosc Endosc Percutan Tech. 2010 Apr;20(2):e73-5. doi: 10.1097/SLE.0b013e3181d874a0. PubMed [citation] PMID: 20393326

38. Witte TN, Danovitch SH, Borum ML, Irani SK. Endoscopic trimming of a rectal self-expanding metallic stent by use of argon plasma coagulation. Gastrointest Endosc. 2007 Jul;66(1):210-1. No abstract available. PubMed [citation] PMID:17591502

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #197

Chronic Atrophic Gastritis: Don’t Miss These Nutritional Deficiencies

April 2020 • Volume XLIV, Issue 4
Craig R. Gluckman

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Chronic atrophic gastritis (CAG) results in the destruction of gastric mucosa parietal cells leading to reduced gastric acid secretion and decreased intrinsic factor (IF) production. The consequence of which is achlorhydria, hypergastrinemia, and IF deficiency. As a result, CAG may lead to the malabsorption (albeit by different mechanisms) of vitamin B12 and iron, causing macrocytic anemia or iron deficiency anemia, respectively. Vitamin B12 deficiency, due to decreased IF production can result in megaloblastic anemia and varying neurologic dysfunction. The mechanism of iron deficiency in CAG is less clear but felt likely due to achlorhydria or concomitant Helicobacter pylori infection. In addition, other vitamin and micronutrient deficiencies (such as vitamin D, calcium and vitamin C) have been known to occur in patients with CAG, although the mechanisms for these have been less well studied. This article will review the nutritional deficiencies as a consequence of CAG.

INTRODUCTION

Chronic atrophic gastritis (CAG) results in atrophy of the gastric body mucosa and the chronic loss of gastric parietal cells. These parietal cells, under the influence of gastrin (from G cells) and histamine (from ECL cells), stimulate acid production and lead to decreased pH in the gastric lumen.1 The parietal cells also control intrinsic factor (IF) production by a different mechanism. This parietal cell loss leads to reduced gastric acid secretion and decreased IF production. The cause of atrophic gastritis (AG) is either (i) the immune-mediated destruction by antibodies (IF and/ or parietal cell) directed against the gastric mucosa (termed chronic atrophic autoimmune gastritis (CAAG)) or (ii) Helicobacter pylori (H. pylori) infection. Regardless of the cause, the net effect of parietal cell loss and gastric atrophy is achlorhydria, which induces G cell hyperplasia and the secretion of additional gastrin resulting in hypergastrinemia.2 Significantly, each of the abovementioned causes of CAG harbor an increased risk for gastric neoplasia, including gastric adenocarcinoma and Type 1 gastric carcinoids, particularly when extensive gastric intestinal metaplasia is present.3 Therefore, in populations at low risk for gastric cancer (like in the U.S.), endoscopic surveillance every 3 years should be offered to patients with extensive atrophic gastritis or intestinal metaplasia.4

CAG leads to the malabsorption of foodbound vitamin B12 due to decreased IF production resulting in megaloblastic anemia (a type of macrocytic anemia) and demyelinating neurologic disease. A deficiency of folate can result in a similar clinical picture. The terms ‘megaloblastic anemia’ and ‘macrocytic anemia’ should not be used interchangeably, as not all causes of macrocytosis are due to vitamin B12 deficiency but all causes of megaloblastic anemia are due to B12 (or folate) deficiency. In contrast, the mechanism for iron deficiency anemia (IDA) in atrophic gastritis is less clearly understood, but likely due to achlorhydria or H. pylori-associated atrophic gastritis. It is therefore vital to exclude atrophic gastritis caused by H. pylori infection in any patient presenting with an unexplained IDA, as this is treatable.

CAAG may occur as part of the polyglandular autoimmune syndrome and may be associated with other autoimmune diseases such as type I diabetes, vitiligo, and thyroid disease; therefore, these associated conditions should be considered during the evaluation of CAG. In addition, other vitamin and micronutrient deficiencies (including vitamin D, calcium and vitamin C) have been known to occur in patients with CAG, although their frequency and likely mechanism of onset is less well understood.

The endoscopic appearance of CAG may not be different from normal mucosa, especially during the early disease state.5 Therefore, if CAG is clinically suspected, the endoscopist at the time of upper endoscopy should perform biopsies according to the updated Sydney protocol (two from the corpus, two from the antrum, and one from the angularis),6 as well as targeted biopsies of any visible lesions. It should be noted there may be endoscopic findings other than gastric body mucosal atrophy such as gastric polyps or Type I gastric neuroendocrine tumors (Image 1).

Vitamin and Micronutrient Deficiencies Vitamin B12 Deficiency

The absorption of food-bound vitamin B12 is mostly dependent on the glycoprotein IF which is produced by gastric parietal cells. The vitamin B12IF complex is ultimately absorbed in the terminal ileum. In CAG, there is a lack of IF production due to parietal cell destruction causing downstream reduced vitamin B12 absorption. Megaloblastic anemia due to vitamin B12 (or folate) deficiency leads to defective production of erythrocytes and DNA synthesis, hence the macrocytic red blood cells. In CAAG, the presence of autoantibodies directed against IF and/or parietal cells results in pernicious anemia (PA). Testing for both antibodies significantly increases their diagnostic performance for diagnosing CAAG and PA, yielding a 73% sensitivity and 100% specificity for PA.7 The immune destruction of parietal cells leads to decreased IF production which results in PA, especially common in Westernized countries and the elderly. The other conditions causing vitamin B12 deficient megaloblastic anemia (Table 1) need to be differentiated from CAAG which causes PA from IF deficiency.

A lack of vitamin B12 affects the two human enzymes that require it, namely methionine synthase (cytoplasm) and methylmalonyl-CoA mutase (mitochondria) and gives rise to elevated levels of homocysteine and methylmalonic acid (MMA), respectively.8 In borderline cases of vitamin B12 deficiency, the elevation of homocysteine and MMA can confirm the diagnosis, especially when other compatible clinical or biochemical findings are present. Interpret homocysteine and MMA levels with caution in renal failure and pregnancy where falsely elevated levels may occur. Elevated plasma homocysteine is now recognized as an independent risk factor for cardiovascular disease and seems to play an important role in the development of dementia, diabetes mellitus and renal disease.9 Homocysteine is also elevated in folate deficiency.

The clinical sequela of vitamin B12 deficiency (Table 2) range from asymptomatic to varying degrees of hematological and neurological dysfunction, which may or may not be reversible with supplementation. The classic neurological presentation of a patient with PA is proprioceptive sensory loss with ataxic gait abnormalities, demyelinating peripheral sensory-motor polyneuropathies and paresthesias. Cognitive changes may also be seen including amnesia, apathy, depression and ultimately more serious cognitive decline. In the most severe forms of vitamin B12 deficiency, there may be complete myelopathy with sub-acute degeneration of the spinal cord and blindness due to optic atrophy. The myriad hematological manifestations include megaloblastic anemia (because of impaired DNA synthesis and erythropoiesis) with pancytopenia despite a hypercellular bone marrow. There appears to be a reduced awareness of CAG and its clinical consequences amongst physicians, often leading to a significant diagnostic delay. This could result in the potential diagnosis of vitamin B12 deficiency being overlooked for many months. A recent study from Italy that looked at 291 patients with CAG found that the median overall diagnostic delay was 14 months (interquartile range [IQR] 4-41), particularly amongst gastroenterologists.10 Clearly there is a need for increased education and awareness of this condition, and treating physicians need to maintain a high index of suspicion. Whether acid blocking drugs like proton pump inhibitors (PPIs) and H2- receptor antagonists can lead to a clinically significant vitamin B12 deficient state remains up for debate. It is unclear if the effects of these drugs on serum vitamin B12 are associated with increased risk of biochemical or functional deficiency (as indicated by elevated blood concentrations of homocysteine and MMA) or clinical deficiency (including megaloblastic anemia and neurologic disorders).11 A recent expert review and best practice advice statement from the American Gastroenterological Association recommended that long-term PPI users should not routinely raise their intake of vitamin B12 beyond the recommended daily allowance, nor should they routinely screen or monitor vitamin B12 levels.12 The route of replacement of vitamin B12 in a deficient patient has also become somewhat of a controversial issue. Most patients with clinical vitamin B12 deficiency have malabsorption and require either intramuscular (IM) or high-dose oral replacement. Those with CAAG causing PA will need lifelong supplementation. A recent Cochrane review by Wang et al. showed that oral and IM vitamin B12 supplementation have similar effects in terms of normalizing serum vitamin B12 levels, but oral treatment costs less.13 However, the quality of evidence was low given the shortage of highquality comparative studies. Therefore, a suggested supplementation regimen would be vitamin B12 at a dose of 1000 mcg administered IM daily or every other day for 1 week, then weekly for 4 to 8 weeks, and then monthly for life, or oral vitamin B12 at a daily dose of 1000 to 2000 mcg for life.14

Iron Deficiency

In patients with CAG, in addition to vitamin B12 deficiency, there may be a preceding or overlapping iron deficiency anemia (IDA) with age being an important factor as to which presents first. Younger patients are more likely to present with features of IDA whereas those over the age of 60, tend to have megaloblastic vitamin B12 deficiency. The variable age-dependent presentation of anemia in patients with CAG reflects the higher prevalence of active H. pylori infection in younger patients.15 As a result, red cell indices like mean cell volume (MCV) may be unreliable in patients with CAG, as two separate or overlapping deficiencies may be present (the one raising the MCV and the other one lowering it), hence it appears within normal limits. The possible role of achlorhydria in the development of iron malabsorption has been suggested in different hypo/ achlorhydria models.16 Low gastric acid secretion results from parietal cell loss. This low gastric acid production leads to decreased food iron solubilization and decreased iron absorption. Therefore, IDA is a common presentation in CAG, but is often overlooked. In a study of 160 patients diagnosed as having autoimmune gastritis by the combined presence of hypergastrinemia and strongly positive antiparietal cell antibodies, 83 (52%) presented with IDA manifested by low serum ferritin levels, low transferrin saturations, and microcytic anemia.17 The presence of IDA due to H. pylori infection in patients with CAG is more complex. It has been shown that up to two-thirds of atrophic gastritis patients have evidence of H. pylori infection. This high prevalence suggests the infection could have a specific role in the disease and not just a mere association.18 Therefore, it is essential H. pylori is actively excluded in all patients with CAG (or pernicious anemia), so as not to miss a concomitant IDA. It has also been observed that failure to respond to oral iron treatment was more than twice as common in H. pylori positive patients compared to H. pylori negative patients, suggesting that H. pylori infection alters the response to oral iron treatment in IDA.19 The cure of H. pylori infection is associated with reversal of iron dependence and recovery from IDA.20 Therefore, eradication of H. pylori, together with oral iron replacement, is essential in the management of patients with CAG and IDA.

Vitamin D and Calcium Deficiency

There are limited studies suggesting osteopenia and osteoporosis (due to vitamin D and calcium malabsorption) are more common in conditions associated with hypo/achlorhydria, such as post gastrectomy, chronic PPI users and atrophic gastritis. The precise mechanism leading to this association is unclear and the available evidence is controversial. A recent study from Italy evaluated the prevalence of 25-OH-vitamin D (25(OH) D) deficiency in a cohort of 87 patients with CAG. They found in the CAG group, the mean 25(OH) D levels were significantly lower than in the control group (18.8 vs. 27.0 ng/ ml, p < 0.0001). Additionally, the CAG patients with moderate/severe gastric atrophy had lower 25(OH) D values as compared to those with mild atrophy.21 This suggests that the severity of gastric atrophy is associated with the degree of 25(OH) D malabsorption. As indicated above, any condition leading to hypo/achlorhydria can result in calcium malabsorption by unclear mechanisms. Gastric acid plays an important role in calcium absorption as it increases the dissolution and ionization of poorly soluble calcium.22 Recker et al. found that in patients with achlorhydria, the absorption of calcium carbonate was less than in controls with normal gastric acid.23 Further studies are clearly needed to evaluate whether vitamin D and calcium malabsorption in CAG patients is clinically significant and warrants monitoring. It also has been suggested that vitamin B12 deficiency in patients with atrophic gastritis likely plays a role in vitamin D deficiency (and calcium malabsorption). Vitamin B12 deficient patients have less osteoblastic activity and bone formation24 and greater risk of bone fracture.25 Of note, both men and women with lower vitamin B12 levels had lower average bone mineral density than controls.26 More research into the relationship between vitamin B12, vitamin D and calcium deficiency, and their potential association with reduced bone mineral density and increased fracture risk in patients with CAG, is needed.

Vitamin C Deficiency

The likely mechanism of vitamin C deficiency in CAG appears to be different from those described above. Older studies proposed a deficiency of vitamin C due to malabsorption, insufficient intake, increased metabolic requirement and rapid destruction in the GI tract.27 Elevated pH (from achlorhydria) and bacterial overgrowth may also be a factor.28 Alt et al. evaluated the effect of pH on ascorbic acid stability in vitro and demonstrated the destruction of 65% of the ascorbic acid at pH 7.95 vs only 14% at pH 1.45.29 The antioxidant effects of vitamin C may provide protection from gastric atrophy and a reduction in the incidence of gastric cancer.30 Further studies into the consequences of vitamin C deficiency in gastric diseases are clearly needed.

CONCLUSION

Atrophic gastritis, regardless of its cause, leads to nutritional deficiencies through parietal cell atrophy and the resulting achlorhydria. Vitamin B12 deficiency is well described, but often diagnosed late. A patient with an unexplained iron deficiency anemia should have atrophic gastritis (and concomitant H. pylori) excluded. The significance of vitamin D, calcium and vitamin C malabsorption in chronic atrophic gastritis remains to be seen.

References

1.Gluckman CR, Metz DC. Gastric Neuroendocrine Tumors (Carcinoids). Current Gastroenterology Reports (2019) 21: 13.

2.Sato Y. Clinical features and management of type 1 gastric carcinoids. Clin J Gastroenterol (2014) 7:381386.

3. Lahner E, Carabotti M, Annibale B. Atrophic body gastritis: Clinical presentation, diagnosis, and outcome. EMJ Gastroenterol. 2017;6[1]:75-82.

4. Banks M, Graham D, Jansen M, et al. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut. 2019 Sep;68(9):1545-1575.

5. Massironi S, Zilli A, Elvevi A, et al. The changing face of chronic autoimmune atrophic gastritis: an updated comprehensive perspective. Autoimmunity Reviews 18 (2019) 215- 222.

6. Dixon MF, Genta RM, Yardley JH, et al. Classification and grading of gastritis. The updated Sydney system. International workshop on the histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996;20:1161–818827022.

7. Lahner E, Norman GL, Severi C, et al. Reassessment of intrinsic factor and parietal cell autoantibodies in atrophic gastritis with respect to cobalamin deficiency. Am J Gastroenterol 2009;104(8):2071-9.

8. Rébeillé F, Ravanel S, Marquet A, et al. Roles of vitamins B5, B8, B9, B12 and molybdenum cofactor at cellular and organismal levels. Nat Prod Rep 2007;24: 949-962.

9. Rodriguez-Castro KI, Franceschi M, Noto A, et al. Clinical manifestations of chronic atrophic gastritis. Acta Biomed. 2018;89(8-S):88–92.

10. Lenti MV, Miceli E, Cococcia S, et al. Determinants of diagnostic delay in autoimmune atrophic gastritis. Aliment Pharmacol Ther. 2019 Jul;50(2):167-175.

11. Miller JW. Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications. Adv Nutr 2018; 9:511S–518S.

12. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology 2017;152(4):706–15.

13. Wang H, Li L, Qin LL, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No.: CD004655.

14. Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013; 368:2041-2042.

15. Bergamaschi G, Di Sabatino A, Corazza GR. Pathogenesis, diagnosis and treatment of anemia in immune-mediated gastrointestinal disorders. Br J Haematol, 2018; 182: 319-329.

16.Annibale B, Capurso G, Delle Fave G. Consequences of Helicobacter pylori infection on the absorption of micronutrients. Dig Liver Dis 2002; 34 Suppl 2: S72S77.

17. Hershko C, Ronson A, Souroujon M, et al. Variable hematologic presentation of autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion. Blood 2006; 107: 1673-1679.

18. Annibale B, Negrini R, Caruana P, et al. Two thirds of atrophic body gastritis patients have evidence of Helicobacter pylori infection. Helicobacter. 2001; 6:225-233.

19. Hershko C, Hoffbrand AV, Keret D, et al. Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia. Haematologica Jan 2005, 90 (5) 585-59.

20. Annibale B, Marignani M, Monarca B, et al. Reversal of Iron Deficiency Anemia after Helicobacter pylori Eradication in Patients with Asymptomatic Gastritis. Ann Intern Med. 1999; 131:668–672.

21. Massironi S, Cavalcoli F, Zilli A, et al.Relevance of vitamin D deficiency in patients with chronic autoimmune atrophic gastritis: a prospective study. BMC Gastroenterology (2018) 18:172.

22. Cavalcoli F, Zilli A, Conte D, et al. Micronutrient deficiencies in patients with chronic atrophic autoimmune gastritis: A review. World J Gastroenterol 2017 January 28; 23(4): 563-572.

23. Recker RR. Calcium absorption and achlorhydria. N Engl J Med 1985; 313: 70-73.

24. Carmel R, Lau KH, Baylink DJ, et al. Cobalamin and osteoblast-specific proteins. N Engl J Med 1998; 319: 70–75.

25. Eastell R, Vieira NE,Yergey AL, et al. Pernicious anemia as a risk factor for osteoporosis. Clin Sci (Lond) 1992; 82:681– 685.

26. Tucker KL, Hannan MT, Qiao N, et al. Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study. J Bone Miner Res 2005; 20: 152-158.

27. Ludden J, Flexner J, Wright I. Studies on ascorbic acid deficiency in gastric diseases: Incidence, diagnosis, and treatment. Am J Digest Dis 1941; 8: 249-252.

28. Kendall AI, Chinn H. Decomposition of ascorbic acid by certain bacteria. J Infect Dis. 1938; 62:330–336

29. Alt HA, Chinn H, Farmer CJ. The blood plasma ascorbic acid in patients with achlorhydria. Am J Med Sci. 1939; 197:222–232.

30. Aditi A, Graham DY. Vitamin C, gastritis, and gastric disease: a historical review and update. Dig Dis Sci. 2012;57(10):2504–2515.

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MEDICAL BULLETIN BOARD

Prometheus Biosciences Launches Monitr™ Covid-19 Assistance Program (M.C.A.P.)

April 2020 • Volume XLIV, Issue 4

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The PROMETHEUS® Monitr™ Crohn’s Disease Test is being offered through M.C.A.P., at no cost to qualifying patients* Prometheus’ Monitr CD test, a noninvasive, serum-based test that can aid in the assessment of endoscopic disease activity in conjunction with other clinical findings

SAN DIEGO, CA – Prometheus Biosciences, Inc. (“Prometheus”), a biopharmaceutical company committed to the discovery, development, and commercialization of a broad portfolio of novel precision therapeutics and diagnostics for patients living with unmet needs in gastroenterology and autoimmune diseases, announced that it has launched the Monitr™ COVID-19 Assistance Program (M.C.A.P.) to provide adult Crohn’s disease (CD) patients with access to this valuable test.

“During these unprecedented times, our focus at Prometheus continues to remain on the patients we serve. With the launch of M.C.A.P., we are providing qualifying adult CD patients impacted by COVID-19 with an effective disease-monitoring test at no cost,” said Mark McKenna, President and CEO of Prometheus. “We believe that the adoption of this program by GI physicians could minimize the burden on Crohn’s disease patients as the novel coronavirus continues to impact the global healthcare system. We are working on continued access to our mobile phlebotomy services to facilitate sample collection and mitigate the need for your patients to engage in any unnecessary travel.”

As a direct result of the COVID-19 pandemic, many healthcare providers have canceled or may soon cancel elective outpatient colonoscopies that are used to assess the mucosal status of CD patients. As a result, physicians may need to make therapy decisions for patients with CD without the objective data provided by colonoscopy regarding disease activity. Prometheus’ commercially-available Monitr test, a first-of-its kind, noninvasive serum test aids in distinguishing CD patients in endoscopic remission from those with active disease, enabling more informed treatment management decisions. The Monitr test has been validated, and results presented in Gastroenterology.

Maria T. Abreu, M.D., Director of the Crohn’s and Colitis Center, University of Miami Health System, commented, “As physicians who care for IBD patients, we want to make the best decisions about medications for our patients, especially in the face of COVID-19. Most of us have taken the measure to delay colonoscopies in our patients and we don’t know when it will be safe to have patients return for colonoscopies. I am happy that our Crohn’s patients can benefit from Monitr as a way of determining active disease or healed mucosa. Having patients avoid hospitals and laboratories all together is great during this special situation.”

About the Monitr COVID-19 Assistance Program (M.C.A.P.)

Prometheus Biosciences launched its Monitr COVID-19 Assistance Program to support patients with adult Crohn’s disease. Through this assistance program, Prometheus is providing the Monitr test at no charge for those patients who have lost employment and/or commercial insurance coverage as a result of the COVID-19 outbreak.* This program will be available to all qualifying patients from March 23, 2020 through June 1, 2020 where Prometheus Biosciences acts as the billing entity. For all other patients, Prometheus’ existing financial assistance programs are still available. In addition, Prometheus is also working on continued, uninterrupted access to mobile phlebotomy services to facilitate sample collection and mitigate the need for patients to engage in any unnecessary travel. If you have any questions on how to order the Prometheus Monitr CD test, please contact Prometheus’ client services team at 888-423-5227.

About Prometheus Biosciences, Inc.

Prometheus Biosciences, Inc., is a biopharmaceutical company committed to the discovery, development, and commercialization of a broad portfolio of novel precision therapeutics and diagnostics for patients living with unmet needs in gastroenterology and autoimmune diseases. Prometheus Biosciences, Inc., created through the June 2019 acquisition of Prometheus Laboratories by Precision IBD, is headquartered in San Diego, California.

For more information about Prometheus, please visit us at: prometheusbiosciences.com

Program will be available to all qualifying patients from March 23, 2020 through June 1, 2020 where Prometheus Biosciences acts as the billing entity.

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FRONTIERS IN ENDOSCOPY, SERIES #61

Pancreas Divisum: Evaluation and Treatment of a Persistently Controversial Anatomic Finding

April 2020 • Volume XLIV, Issue 4
Taylor Frost,Douglas G. Adler

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INTRODUCTION

Pancreas divisum (literally, “divided pancreas”) is the most common anatomic variant of the pancreas and is thought to exist in 5-10% of the population.36,37 Pancreas divisum is the result of the failed fusion of the dorsal and ventral pancreatic buds early in development, resulting in the majority of the pancreas being drained through the minor papilla. (Figure 1) In patients with normal anatomy, the majority of the pancreas drains through the major papilla. More formally stated, in patients with pancreas divisum, the variant pancreatic ductal anatomy leads to the relatively large dorsal pancreas segment being drained through the minor papilla while the smaller ventral bud drains through the major papilla. There is no known etiology for pancreas divisum however, some genetic abnormalities including mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Serine Protease Inhibitor Kazal-type 1 (SPINK1) genes have been associated with the condition.1 CFTR mutations may be present in up to 22% of patients with pancreas divisum who develop pancreatitis.2

The majority of patients with pancreas divisum will remain clinically asymptomatic and may only be diagnosed incidentally in the context of an imaging study ordered for another indication. However, some patients may be found to have pancreas divisum in the setting of a history of, or investigation into, episodes of pancreatitis.3 It has been proposed that a relatively stenotic minor papilla may predispose patients with pancreas divisum to recurrent episodes of pancreatitis.15 As such, in some cases patients are recommended to undergo therapy for pancreas divisum, usually in the form of endoscopic minor papilla sphincterotomy and/or endoscopic pancreatic duct stenting and, rarely, via surgical intervention. (Figure 2) This approach can be technically challenging, remains controversial, and is still being debated in the literature. This review article will focus on the literature regarding endoscopic intervention for symptomatic pancreas divisum and briefly touch upon the role of surgical intervention for definitive management.

Treatment: Endoscopic Intervention

Endoscopic therapy for symptomatic pancreas divisum has been well documented since the early 1980’s. However, given the relative rarity of the condition, there has been a paucity of high quality and well-defined studies that evaluate the efficacy of endoscopic intervention in this complex and somewhat difficult-to-study group of patients. Furthermore, the modality of intervention has evolved over this time period as well and has included minor and major papilla cannulation with balloon dilation, minor papilla stenting and a combination of minor papilla sphincterotomy and stenting.4,5,6,7,8,9,10,11,12,13

As a clinical entity, patients with symptomatic pancreas divisum often manifest in three groups, which include recurrent acute pancreatitis, chronic pancreatitis, and pancreatic-type pain. It should be stressed that the majority of patients with pancreas divisum will be asymptomatic. The particular manifestation of pancreas divisum encountered clinically is important as it may predict long term response to both endoscopic and surgical interventions.14

The definition of recurrent acute pancreatitis varies depending on the study but is optimally defined as pancreas divisum with two or more episodes of pancreatitis, a serum amylase or lipase level greater than three times the upper limit of normal, abdominal pain, and imaging that is suggestive of pancreatic inflammation without chronic changes. If abdominal imaging demonstrates morphological changes to the pancreatic duct or parenchyma then chronic pancreatitis is more likely to be present. If none of these criteria are present but the patient continues to experience abdominal pain that is characteristically similar to that of pancreatitis then pancreatic-type pain can be considered.

Recurrent Acute Pancreatitis

It has been hypothesized that recurrent acute pancreatitis can develop secondary to the reflux of pancreatic secretions across the dorsal pancreatic duct due to a relatively stenotic minor papilla and, although manometric data has demonstrated mixed results, endoscopic intervention has been of some benefit in select patients with recurrent acute pancreatitis.15,4,16 In perhaps the most well described study in the literature, Lans et al. (1992) conducted a prospective randomized controlled trial of 19 patients with symptomatic pancreas divisum thought to be due to recurrent acute pancreatitis. In this study the authors found that patients who underwent endoscopic dorsal duct dilation followed by stent placement for one year had nearly a 100% response rate with only one episode of recurrent pancreatitis (due to stent occlusion), no hospitalizations, and significantly fewer emergency room visits for abdominal pain compared to controls. In addition, the patients who underwent endoscopic intervention reported subjective improvements in symptoms and general overall well being. Unfortunately, these results have not entirely been reflected elsewhere in the literature although most studies are difficult to interpret given less well-defined patient populations, varying definitions of successful endoscopic treatment, and a lack of long-term follow-up. Furthermore, this study also did not include minor papilla sphincterotomy, thus limiting its generalizability.

Several retrospective studies that utilized sphincterotomy in combination with or without pancreatic duct stenting have described clinical success rates ranging from 53-84% after a single ERCP session in patients with recurrent acute pancreatitis that was felt to be due to pancreas divisum.12,17,18,19,20 There is an additional study that suggests that this initial success rate may be increased with subsequent ERCP sessions, but this approach is uncommonly undertaken in the absence of recurrent stricturing at the site of the minor papilla.21 A recent meta-analysis demonstrated a pooled response rate of 76% in patients with recurrent acute pancreatitis who underwent minor papilla sphincterotomy, minor papilla sphincteroplasty, dorsal duct stenting, or a combination procedure. In this study, the rate of improvement following endoscopic intervention relied upon the individual study definition of success, which may limit the applicability of the results. A subgroup of patients in this meta-analysis who underwent dorsal duct stenting alone without sphincterotomy experienced higher rates of success when compared to those who underwent combined sphincterotomy with stenting.22 Although few in number, studies evaluating the long-term efficacy of endoscopic intervention in patients with pancreas divisum suggest that improvement in symptoms may be sustained in those who initially respond to therapy with longterm response rates ranging from 50-85%.12,23

Chronic Pancreatitis

Evidence for endoscopic therapy in patients with chronic pancreatitis and pancreas divisum is sparse. Some studies have reported no improvement in symptoms following endoscopic therapy while others have demonstrated long-term response rates between 30-50% at five years.4,24,21 It is somewhat difficult to reconcile these diverse success rates. Typically, response rates are defined as a reduction in subjective pain level, reduced narcotic use, or a reduction in hospital admissions. It should be noted that up to 45% of patients may require surgical management within 5 years of the initial endoscopic intervention.10 Dorsal duct dilation on imaging may reflect more severe pancreatic disease. Distal intrapancreatic bile duct strictures have been reported in advanced calcific pancreatic disease and may be resistant to endoscopic intervention.25,26 One study found that patients with dorsal duct dilation required 3 or more ERCP sessions over the course of their disease and progressed to surgical intervention at a higher rate.14 A recent study that utilized stricture dilation and stent exchange based on symptoms was able to avoid subsequent surgical intervention in 95% of patients. However, extracorporeal shock wave lithotripsy was performed in this study for patients with dorsal duct caliculi, which may have influenced the overall response rate.27

Pancreatic Type-Pain

The evidence for endoscopic intervention in patients with only pancreatic type-pain in the setting of pancreas divisum suggests that the vast majority of patients undergoing endoscopic intervention will not experience a change in symptoms. Individual studies have reported that between 20-40% of patients may subjectively report improvements in pain. However, no statistically significant effect has been demonstrated.18,28,29 A meta-analysis of 10 studies with 131 patients estimated a pooled response rate of 48% although the effect of endoscopic intervention was considered to be equivocal and no long-term data are available.22 Furthermore, there has been no difference demonstrated between patients who undergo sphincterotomy and stenting verse stenting alone in patients with pancreatic type-pain.21

Taken as a whole, endoscopic intervention for symptomatic pancreas divisum appears to be of most benefit in those with well-defined recurrent acute pancreatitis without another clear etiology. There is some evidence that patients with chronic pancreatitis may benefit from endoscopic therapy; however, a large portion may still progress to surgical intervention or require multiple ERCP sessions. In patients with pancreatic type-pain endoscopic therapy is unlikely to yield any benefit and long-term data are lacking.

The potential benefits of endoscopic intervention must be weighed against the known complications associated with minor papilla interventions. A recent meta-analysis of balloon dilation, sphincterotomy with or without stenting, or stenting alone performed for symptomatic pancreas divisum reported a post-ERCP pancreatitis rate of 10%.22 This rate is above the known rate of pancreatitis following ERCP and may reflect the variant anatomy and complexity of the procedure being performed.30 Minor papilla restenosis is an established delayed complication and can occur in up to 23% of patients, with higher rates in patients who undergo minor papilla sphincterotomy without stenting.11,3,29

Surgical Interventions

While most cases of symptomatic pancreas divisum are treated endoscopically there are some patients who will require surgical intervention. Surgical approaches include surgical sphincteroplasty of the minor papilla, duodenum-preserving pancreatic head resection, partial pancreaticoduodenectomy (Whipple procedure), the Frey procedure, and the Nakao procedure. The Frey procedure consists of the local resection of the pancreatic head with longitudinal drainage of the pancreatic duct while the Nakao procedure includes complete pancreatic head resection with segmental duodenectomy, pancreaticogastrostomy and end to-end duodenoduodenostomy. To date there are no randomized controlled trials comparing endoscopic and surgical interventions for symptomatic pancreas divisum. A recent systematic review with quantitative analysis of 1289 patients who were treated endoscopically and 598 patients who were treated surgically suggested that surgery may have a higher success rate with lower complications and need for re-intervention. However, the authors cautioned that selection bias may have contributed to an unequal distribution and concluded that existing evidence does not allow for a definitive recommendation for clinical decision making.31 One observational study found that patients who considered a first-line therapy in patients who remain symptomatic but are without evidence of pancreatic fibrosis. Pancreatic head resection should be considered in those with fibrotic alterations of the pancreatic head.35

CONCLUSION

Pancreas divisum is a common congenital abnormality of the pancreas and is thought to be present in 5-10% of the population.36,37 A small subset of patients with pancreas divisum have been observed to develop attacks of recurrent acute pancreatitis that can then progress to chronic pancreatitis or persistent pancreatic type pain. Endoscopic intervention with sphincterotomy and stenting or stenting alone has been shown to resolve or improve symptoms in some patients with recurrent acute pancreatitis and may be of some benefit in patients with chronic pancreatitis. This has led some studies to recommend endoscopy as the first line therapy.31,33 However, some individuals may continue to remain symptomatic despite seemingly adequate endoscopic therapy and eventually require surgical management, which itself may not be curative. An individualized surgical approach is recommended with consideration of papilla reinsertion or pancreatic head resection depending on the morphological changes seen in the pancreas.34,35

References

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2. Choudari CP, Imperiale TF, Sherman S, Fogel E, Lehman GA. Risk of pancreatitis with mutation of the cystic fibrosis gene. Am J Gastroenterol. 2004 Jul;99(7):1358-63. PubMed PMID: 15233679.

3. Lehman GA, Sherman S. Pancreas divisum. Diagnosis, clinical significance, and management alternatives. Gastrointest Endosc Clin N Am. 1995 Jan;5(1):145-70. Review. PubMed PMID: 7728342.

4. Satterfield ST, McCarthy JH, Geenen JE, Hogan WJ, Venu RP, Dodds WJ, Johnson GK. Clinical experience in 82 patients with pancreas divisum: preliminary results of manometry and endoscopic therapy. Pancreas. 1988;3(3):248-53. PubMed PMID: 3387418.

5. Lans JI, Geenen JE, Johanson JF, Hogan WJ. Endoscopic therapy in patients with pancreas divisum and acute pancreatitis: a prospective, randomized, controlled clinical trial. Gastrointest Endosc. 1992 Jul-Aug;38(4):430-4. PubMed PMID: 1511816.

6. Siegel JH, Ben-Zvi JS, Pullano W, Cooperman A. Effectiveness of endoscopic drainage for pancreas divisum: endoscopic and surgical results in 31 patients. Endoscopy. 1990 May;22(3):129-33. PubMed PMID: 2103724.

7. Mariani A, Di Leo M, Petrone MC, Arcidiacono PG, Giussani A, Zuppardo RA, Cavestro GM, Testoni PA. Outcome of endotherapy for pancreas divisum in patients with acute recurrent pancreatitis. World J Gastroenterol. 2014 Dec 14;20(46):17468-75. doi: 10.3748/wjg.v20. i46.17468. PubMed PMID: 25516660; PubMed Central PMCID: PMC4265607.

8. Kwan V, Loh SM, Walsh PR, Williams SJ, Bourke MJ. Minor papilla sphincterotomy for pancreatitis due to pancreas divisum. ANZ J Surg. 2008 Apr;78(4):25761. doi: 10.1111/j.1445-2197.2008.04431.x. PubMed PMID: 18366396.

9. Chacko LN, Chen YK, Shah RJ. Clinical outcomes and nonendoscopic interventions after minor papilla endotherapy in patients with symptomatic pancreas divisum. Gastrointest Endosc. 2008 Oct;68(4):667-73. doi: 10.1016/j.gie.2008.01.025. Epub 2008 Apr 24. PubMed PMID: 18436218.

10. Vitale GC, Vitale M, Vitale DS, Binford JC, Hill B. Long-term follow-up of endoscopic stenting in patients with chronic pancreatitis secondary to pancreas divisum. Surg Endosc. 2007 Dec;21(12):2199-202. Epub 2007 May 19. PubMed PMID: 17514389.

11. Attwell A, Borak G, Hawes R, Cotton P, Romagnuolo J. Endoscopic pancreatic sphincterotomy for pancreas divisum by using a needle-knife or standard pull-type technique: safety and reintervention rates. Gastrointest Endosc. 2006 Nov;64(5):705-11. Epub 2006 Sep 1. PubMed PMID: 17055861.

12. Gerke H, Byrne MF, Stiffler HL, Obando JV, Mitchell RM, Jowell PS, Branch MS, Baillie J. Outcome of endoscopic minor papillotomy in patients with symptomatic pancreas divisum. JOP. 2004 May;5(3):122-31. Review. PubMed PMID: 15138333.

13. Kim MH, Lee SS, Kim CD, Lee SK, Kim HJ, Park HJ, Joo YH, Kim DI, Yoo KS, Seo DW, Min YI. Incomplete pancreas divisum: is it merely a normal anatomic variant without clinical implications? Endoscopy. 2001 Sep;33(9):778-85. PubMed PMID: 11558032.

14. Tierney J, Bhutiani N, Brown AN, Richey JS, Bahr MH, Vitale GC. Identifying Factors Predicting Response to Endoscopic Management of Chronic Pancreatitis Secondary to Pancreas Divisum. J Gastrointest Surg. 2019 Mar 18. doi: 10.1007/s11605-019-04122-2. [Epub ahead of print] PubMed PMID: 30887289.

15. Cotton PB. Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis. Gut. 1980 Feb;21(2):105-14. PubMed PMID: 7380331; PubMed Central PMCID: PMC1419363.

16. Staritz M, Meyer zum Büschenfelde KH. Elevated pressure in the dorsal part of pancreas divisum: the cause of chronic pancreatitis? Pancreas. 1988;3(1):108-10. PubMed PMID: 3362837.

17. Yamamoto N, Isayama H, Sasahira N, Tsujino T, Nakai Y, Miyabayashi K, Mizuno S, Kogure H, Sasaki T, Hirano K, Tada M, Koike K. Endoscopic minor papilla balloon dilation for the treatment of symptomatic pancreas divisum. Pancreas. 2014 Aug;43(6):927-30. doi: 10.1097/MPA.0000000000000148. PubMed PMID: 24826883.

18. Lehman GA, Sherman S, Nisi R, Hawes RH. Pancreas divisum: results of minor papilla sphincterotomy. Gastrointest Endosc. 1993 Jan-Feb;39(1):1-8. PubMed PMID: 8454127.

19. Heyries L, Barthet M, Delvasto C, Zamora C, Bernard JP, Sahel J. Long-term results of endoscopic management of pancreas divisum with recurrent acute pancreatitis. Gastrointest Endosc. 2002 Mar;55(3):376-81. PubMed PMID: 11868012.

20. Fogel EL, Toth TG, Lehman GA, DiMagno MJ, DiMagno EP. Does endoscopic therapy favorably affect the outcome of patients who have recurrent acute pancreatitis and pancreas divisum? Pancreas. 2007 Jan;34(1):21-45. Review. PubMed PMID: 17198181.

21. Borak GD, Romagnuolo J, Alsolaiman M, Holt EW, Cotton PB. Long-term clinical outcomes after endoscopic minor papilla therapy in symptomatic patients with pancreas divisum. Pancreas. 2009 Nov;38(8):903 doi: 10.1097/MPA.0b013e3181b2bc03. PubMed PMID: 19672208.

22. Michailidis L, Aslam B, Grigorian A, Mardini H. The efficacy of endoscopic therapy for pancreas divisum: a meta-analysis. Ann Gastroenterol. 2017;30(5):550558. doi: 10.20524/aog.2017.0159. Epub 2017 May 12. PubMed PMID: 28845111; PubMed Central PMCID: PMC5566776.

23. Tringali A, Voiosu T, Schepis T, Landi R, Perri V, Bove V, Voiosu AM, Costamagna G. Pancreas divisum and recurrent pancreatitis: long-term results of minor papilla sphincterotomy. Scand J Gastroenterol. 2019 Mar;54(3):359-364. doi: 10.1080/00365521.2019.1584640. Epub 2019 Mar 17. PubMed PMID: 30880501.

24. Boerma D, Huibregtse K, Gulik TM, Rauws EA, Obertop H, Gouma DJ. Long-term outcome of endoscopic stent placement for chronic pancreatitis associated with pancreas divisum. Endoscopy. 2000 Jun;32(6):452-6. PubMed PMID: 10863910.

25. Abdallah AA, Krige JE, Bornman PC. Biliary tract obstruction in chronic pancreatitis. HPB (Oxford). 2007;9(6):421-8. doi: 10.1080/13651820701774883. PubMed PMID: 18345288; PubMed Central PMCID: PMC2215354.

26. Scott J, Summerfield JA, Elias E, Dick R, Sherlock S. Chronic pancreatitis: a cause of cholestasis. Gut. 1977 Mar;18(3):196-201. PubMed PMID: 856677; PubMed Central PMCID: PMC1411390.

27. Bhasin DK, Rana SS, Sidhu RS, Nagi B, Thapa BR, Poddar U, Gupta R, Sinha SK, Singh K. Clinical presentation and outcome of endoscopic therapy in patients with symptomatic chronic pancreatitis associated with pancreas divisum. JOP. 2013 Jan 10;14(1):50-6. doi: 10.6092/1590-8577/1218. PubMed PMID: 23306335.

28. Coleman SD, Eisen GM, Troughton AB, Cotton PB. Endoscopic treatment in pancreas divisum. Am J Gastroenterol. 1994 Aug;89(8):1152-5. PubMed PMID: 8053426.

29. Kozarek RA, Ball TJ, Patterson DJ, Brandabur JJ, Raltz SL. Endoscopic approach to pancreas divisum. Dig Dis Sci. 1995 Sep;40(9):1974-81. PubMed PMID: 7555452.

30. Andriulli A, Loperfido S, Napolitano G, Niro G, Valvano MR, Spirito F, Pilotto A, Forlano R. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol. 2007 Aug;102(8):1781-8. Epub 2007 May 17. Review. PubMed PMID: 17509029.

31. Hafezi M, Mayschak B, Probst P, Büchler MW, Hackert T, Mehrabi A. A systematic review and quantitative analysis of different therapies for pancreas divisum. Am J Surg. 2017 Sep;214(3):525-537. doi: 10.1016/j.amjsurg.2016.12.025. Epub 2017 Jan 3. Review. PubMed PMID: 28110914.

32. Siegel JH, Ben-Zvi JS, Pullano W, Cooperman A. Effectiveness of endoscopic drainage for pancreas divisum: endoscopic and surgical results in 31 patients. Endoscopy. 1990 May 22(3):129-33. PubMed PMID: 2103724.

33. Ferri V, Vicente E, Quijano Y, Ielpo B, Duran H, Diaz E, Fabra I, Caruso R. Diagnosis and treatment of pancreas divisum: A literature review. Hepatobiliary Pancreat Dis Int. 2019 Aug;18(4):332-336. doi: 10.1016/j. hbpd.2019.05.004. Epub 2019 May 20. Review. PubMed PMID: 31155429.

34. Schlosser W, Rau BM, Poch B, Beger HG. Surgical treatment of pancreas divisum causing chronic pancreatitis: the outcome benefits of duodenum-preserving pancreatic head resection. J Gastrointest Surg. 2005 May-Jun;9(5):710-5. PubMed PMID: 15862268.

35. Schneider L, Müller E, Hinz U, Grenacher L, Büchler MW, Werner J. Pancreas divisum: a differentiated surgical approach in symptomatic patients. World J Surg. 2011 Jun;35(6):1360-6. doi: 10.1007/s00268-011-10769. PubMed PMID: 21472371.

36. Stern CD. A historical perspective on the discovery of the accessory duct of the pancreas, the ampulla ‘of Vater’ and pancreas divisum. Gut. 1986 Feb;27(2):20312. PubMed PMID: 3512385; PubMed Central PMCID: PMC1433212.

37. Stimec B, Bulajić M, Korneti V, Milosavljević T, Krstić R, Ugljesić M. Ductal morphometry of ventral pancreas in pancreas divisum. Comparison between clinical and anatomical results. Ital J Gastroenterol. 1996 FebMar;28(2):76-80. PubMed PMID: 8781998.

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MEDICAL BULLETIN BOARD

Sherman Prize, Inspiring Excellence in Crohn’s And Colitis, Now Accepting Nominations

April 2020 • Volume XLIV, Issue 4

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NAPLES, FL – The Bruce and Cynthia Sherman Charitable Foundation announced its annual call for nominations for the 2020 Sherman Prizes, recognizing exceptionally talented, dedicated individuals working tirelessly to improve outcomes for people with Crohn’s disease and ulcerative colitis, and advancing research that could lead to prevention, remission, and cures.

Established in 2016, the Sherman Prize program is the first of its kind, providing financial prizes and national recognition to individuals who exemplify excellence in Crohn’s disease and ulcerative colitis, also known as the inflammatory bowel diseases (IBDs).

“My wife Cynthia and I created the Sherman Prize to celebrate excellence in IBD and inspire greater advances so fewer families have to face the challenges of these diseases,” said Bruce Sherman, Founder of the Sherman Prize. “It’s been inspiring to see the innovative work being done by brilliant IBD professionals. We’re excited to begin our fifth year and we can’t wait to see who is nominated.”

To date, twelve IBD professionals, representing diverse specialties, have been honored through the Prize program. They include physician scientists, a pediatric IBD specialist, a colorectal surgeon, a psychiatrist specializing in IBD and a physician assistant. To learn more about the many ways they are making life better for people with IBD, watch their tribute films at ShermanPrize.org.

Nominations for the 2020 Prizes may be submitted at ShermanPrize.org into the summer. A final deadline will be announced later in the spring. The Prizes will be presented December 10 at the Advances in IBD (AIBD) conference in Orlando, Florida.

About the Sherman Prize Program

The Sherman Prize program honors out-of-the-box thinkers from a variety of professional disciplines who represent “Excellence in Crohn’s and Colitis” in their chosen endeavors, having dedicated their careers to the fight to overcome IBD.

Two $100,000 Sherman Prizes are awarded annually to IBD clinicians, surgeons, researchers and/or academics, recognizing exceptional and pioneering contributions that transform the care of people with IBD. This Prize honors visionaries who are driven to solve IBD’s most difficult challenges and whose work inspires future innovators.

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

Sherman Prize honorees are selected by the Sherman Prize Board of Directors, with guidance from the Sherman Prize Selection Committee, chaired by Dr. Dermot P.B. McGovern, the Joshua L. and Lisa Z. Greer Endowed Chair in Inflammatory Bowel Disease Genetics at CedarsSinai. Joining him on the Selection Committee are Dr. Lee Denson, Cincinnati Children’s Hospital Medical Center; Dr. Mark Gerich, University of Colorado Crohn’s and Colitis Center; Dr. Sunanda Kane, Mayo Clinic; and Dr. Amy Lightner, Cleveland Clinic.

Full eligibility guidelines and guidance on how to submit a nomination may be found at: ShermanPrize.org

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #28

Approach to a Patient with a Liver Lesion

April 2020 • Volume XLIV, Issue 4
Laura M. Kulik

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The presence of a liver lesion undoubtedly causes significant stress and anxiety not only for the patient but also for health care providers. It is important to realize that most liver lesions can be accurately diagnosed utilizing distinguishing features on imaging, laboratory data and clinical history. In lesions that remain indeterminate, a biopsy of the lesion may be warranted. Reviewing older imaging studies can provide invaluable information regarding the stability of the lesion in question and need for additional evaluation.

Liver lesions in the setting of cirrhosis substantially alter the level of concern and clinical approach to testing. Aggregate data, including patient history, laboratory results (to calculate the the aspartate aminotransferase to platelet ratio index, or APRI), evidence of portal hypertension (pHTN) on imaging and physical signs suggestive of chronic liver disease should be used to assess patients individually.

Benign Hepatic Lesions

Hepatic hemangioma, focal nodular hyperplasia (FNH) and hepatic adenoma (HA) are the most common benign liver lesions. The European Association for the Study of the Liver (EASL) has comprehensive guidelines on the management of benign liver lesions.1 When considering if surgical resection is warranted in a patient with a benign liver lesion, there are key questions to consider: 1. Has there been growth of the lesion? 2. Is the lesion atypical or the diagnosis in question? 3. Is the patient having symptoms that could be attributed to the lesion? Magnetic resonance imaging (MRI) is the recommended imaging modality to most accurately characterize suspected benign liver lesions.

Hepatic hemangioma, a blood filled cavity lined by a single layer of epithelial cells that derives its blood supply from the hepatic artery, is the most common benign liver lesion. Thought to be congenital, hemangiomas are more common in woman than men. In contradistinction to other common benign liver lesions, hemangiomas can be seen in cirrhosis, however with less frequency and often diminished in size. These lesions demonstrate avid T2 enhancement on MRI. When small, they may lack the classis features such as centripetal enhancement or a “filling” in, so they must be distinguished from a malignancy in cirrhosis, particularly intrahepatic cholangiocarcinoma (iCCA). Most hemangiomas are less than 5 cm; when greater than 10 cm they are known as a giant hemangioma and size does not correlate with symptoms. When imaging features are consistent with a typical hemangioma, follow up imaging is not required. If a confident diagnosis cannot be made with imaging, a liver biopsy is not contraindicated, however, there must be the presence of normal liver parenchyma between the capsule and the margin of the lesion to minimize complications. Those with symptoms related to a hemangioma or a gaint hemangioma should be evaluated in a multidisciplinary clinic.

Thought to occur as a result of a congenital anomaly as a result of a venous infarct, which leads to arterialization of the affected tissue, the next most common benign liver lesion is FNH. FNH is more common in females (90%), located in the right lobe and generally solitary (conditions that are associated with multiple FNHs include: Budd Chiari syndrome, obliterative portal venopathy, post treamtnet with oxaliplatin).2 A vital feature that aids in distinguishing FNH from HA is the presence of bile ducts and kuffer cells in the former. Using a biliary agent, such as Eovist or Multihance, can help radio graphically differentiate FNH from HA. An MRI is nearly 100% specific for FNH. The hallmark radiographic sign of FNH is a central scar, which represents a corkscrew artery, however in small lesions this may not be present. In lesions less than 3 cm, a contrast enhanced ultrasound (US) may be more accurate. While there is no supporting evidence that FNH have any malignant potential, it can mimic a very rare malignancy, fibrolamellar carcinoma (approximately 200 cases per year reported worldwide) due to the presence of a calcified central scar seen in 55%. Similar to hemangioma, there is no direct correlation with symptoms and size, and resection is rarely needed.

Hepatic adenomas are the least common but most concerning (risk of bleeding and development of hepatocellular carcinoma (HCC) related to size) of the benign liver lesions. The exact incidence of HA is unknown but is 10 times less common than FNH. The classic risk factors have been use of estrogen and androgens. They are more common in females than males, 10:1, and are usually single. While the incidence of HA is declining related to oral contraceptive pill (OCP) use, it is rising due to obesity and the metabolic syndrome, often leading to multiple HA. For males, resection is recommended for HA regardless of size. In females, lifestyle changes (discontinuation of OCP and weight loss) are recommended, with repeat imaging in six months. If the lesion decreases to less than 5 cm, repeat MRI in one year is recommended. If the lesion remains greater than 5 cm, repeat imaging in an additional six months is recommended. If the lesion increases in size by 20% or more, resection is indicated.

The risk of bleeding is highest in adenomas that are larger than 5 cm and exophytic. Additional risk factors for hemorrhage include use of OCPs in the last six months, pregnancy, and the inflammatory subtype (described below). When hemorrhage does occur with HA, embolization by interventional radiology should be performed to control bleeding. Emergent resection is associated with higher mortality rates.

A sub-classification of HAs was initially described in 2006 and updated in 2017.3 Associated with obesity and alcohol use, the lowest risk of degeneration to HCC is in the subtype HNF (inactivated hepatocyte nuclear factor). On imaging there is diffuse steatosis within the lesion. The inflammatory HA carries the highest risk of bleeding and also has a risk of HCC. The highest risk of developing HCC is seen in the beta catenin activated HA.

Pregnancy is no longer considered a contraindication in females with HA larger than 5 cm. If it is larger than 5 cm or there is a history of prior bleeding, resection prior to pregnancy should be discussed. There is currently no evidence based- algorithm for the management of HA in pregnancy. US every 6-12 weeks to monitor for growth is recommended. If a lesion is noted to be growing, embolization can be performed. The highest risk of bleeding during pregnancy is in the third trimester and carries a high mortality rate.

Malignant Hepatic Lesions

When evaluating a lesion that is concerning for malignancy, determining the presence of underlying liver disease, specifically cirrhosis, is important as cirrhosis predisposes patients to HCC as well as iCCA. Other malignant lesions are unrelated to the presence of cirrhosis.

The most common primary liver cancer is HCC, with 80 – 90% of cases occurring in patients with cirrhosis. In 2016, data from the CDC showed a 43% increase in mortality in the United States during the period of 2000-2016. This is thought to be due to the rising incidence of HCC with fairly steady 10-year mortality rates due to HCC. HCC is the leading cause of mortality in patients with cirrhosis with an estimated 1/3 of patients developing HCC in their lifetime. The diagnosis of HCC with known cirrhosis can be made based on radiographic findings without the need for a pathologic confirmation with a biopsy. The presence of arterial enhancement with washout in the venous phase is diagnostic if HCC, regardless of the alpha-fetoprotein (AFP) level (normal in up to 30% of tumors). Arterial enhancement, due to increased hepatic artery blood flow related to angiogenesis, promotes tumor growth and spread.

The American Association for the Study of Liver Diseases (AASLD) recommends HCC surveillance in patients with cirrhosis, regardless of etiology, every six months with an US, with optional AFP level.4 Surveillance is not recommended in patients with Child Pugh C cirrhosis unless they are listed for transplant. The rationale is that mortality will be driven by decompensated cirrhosis and therapy for HCC, if found, is supportive in the presence of significantly impaired liver function. If a lesion on US is detected to be greater than 1 cm, contrast enhanced imaging with computed tomography (CT) or MRI is used to make a diagnosis of HCC.

The liver imaging reporting and data system (LIRADS) was developed by the American College of Radiology with the goal of standardizing the reporting of liver lesions in patients at risk for HCC. There are 5 categories ranging from definitely benign (LI-RADS 1) to definitely malignant (LIRADS 5). A LI-RADS 5 lesion is subdivided based on size: 5A is ≥ 1 cm & < 2 cm and 5B is ≥ 2 cm & ≤ 5 cm. For both of these, a diagnosis of HCC requires the presence of non-rim arterial phase hyperenhancement (APHE) and non-peripheral washout and/or 50% increase or more in size in six months.5 The probability of HCC being present is shown based on the respective LI-RADS category (Table 1).

Liver transplant (LT) provides the best chance for long term overall survival by removing not only the carcinoma but also the cirrhotic liver. Unfortunately, there remains a shortage of organs to allow transplant in all that are listed. Additionally, patients with HCC tend to have preserved liver function and thus a low model for end-stage liver disease (MELD) score. In order to overcome a disadvantage in patients with HCC and a low MELD score, patients with HCC are given a “boost”, or MELD upgrade. While a lesion 1 cm or larger can be diagnosed as HCC based on characteristics seen on contrast enhanced imaging, unless a lesion is a 5A, there is not an MELD HCC upgrade. Once a lesion is 2 cm (T2 lesion), an HCC MELD upgrade is awarded. The prioritization for HCC meeting T2 criteria has evolved since the inception of the MELD allocation system with a lowering in prioritization for HCC with each reiteration in order to make access to an organ more equitable between patients with HCC and those without cancer who are listed with their biological MELD. Currently patients are given an increase in MELD score after a six month waiting period to ensure that the tumor does not harbor aggressive biological behavior that would become more obvious after a period of six months. Patients must have an AFP < 1000 at the time of listing, irrespective of tumor burden. The MELD upgrade is a calculation of the average MELD at the time of LT in each respective Organ Procurement Organization – 3 points.

Cholangiocarcinoma is the second most
common primary hepatic tumor. iCCA is the least common, followed by distal CCA and perihilar CCA (most common). Similar to HCC, the incidence of iCCA has increased and shares risk factors with HCC (cirrhosis, chronic viral hepatitis, alcohol excess, diabetes, and obesity). However, in contrast to HCC, iCCA can occur in patients with a normal architectural liver. The prognosis with iCCA is poor with 5-year overall survival rates under 5%. Currently patients with cirrhosis diagnosed with iCCA are not granted a MELD upgrade for LT due to poor outcomes. It is critical to distinguish a lesion as HCC versus iCCA. Generally these two entities can be distinguished on imaging however if not, then a biopsy of the lesion is warranted. The key radiographic findings in iCCA include progressive arterial enhancement and a lack of washout; ancillary features included capsular retraction and dilated peripheral bile ducts. Surgical resection has been the mainstay of therapy.

Other malignant lesions in the liver that are not related to the presence of cirrhosis include metastatic disease, angiosarcoma and hepatic epithelioid hemangioendothelioma (HEHE). Hepatic spread of other primary malignancies is rare in cirrhosis due to alterations in portal blood flow; the exception is colorectal adenocarcinoma, which has been reported in cirrhosis. Angiosarcoma carries a dismal prognosis with two-year survival of only 3%. Mortality is generally due to tumor rupture (high vascularity) or liver failure due to replacement of the liver with tumor. Risk factors include vinyl chloride, arsenic, cyclophosphamide, anabolic steroids, and OCP. Angiosarcoma is an absolute contraindication for LT. Treatment is resection, when possible, and chemotherapy. Lastly, HEHE is a very rare tumor of vascular origin, which is seen more commonly in middle age females. It has a more favorable prognosis compared to other hepatic malignancies, as it is generally slow growing. Treatment for HEHE includes resection, LT (>10 nodules or >4 involved hepatic segments) and anti-vascular endothelial growth factor (anti-VEGF) therapy.

CONCLUSION

Liver lesions require a careful approach to ensure correct diagnosis and therapy. It is vital to determine if a patient has cirrhosis or chronic liver disease, as this will alter the approach to a liver lesion. Fortunately, key radiographic features can help distinguish the most common benign lesion from each other and generally can be managed conservatively.

References

1. EASL Clinical Practice Guidelines on the management of benign liver tumours. European Association for the Study of the Liver (EASL) Journal of Hepatology 2016;65 :386–398

2. Furlan A, Brancetelli G, Burgio MD et al. Focal Nodular Hyperplasia After Treatment With Oxaliplatin: A Multiinstitutional Series of Cases Diagnosed at MRI. AJR 2018;210:775-79.

3. Nault JC, Couchy G, Balabaud C et al. Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation. Gastroenterology. 2017 Mar;152(4):880-894

4. Heimback J, Kulik LM, Finn R et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67(1); 358-380.

5. American College of Radiology Liver Imaging Reporting and Data System version 2018 core Available from: https://www.acr.org/Clinical-Resources/Reporting-andData-Systems/LI-RADS

6. Marrero JA, Kulik LM, Sirlin CB et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Disease. Hepatology 2018;68,(2):723-750.

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FELLOWS’ CORNER

A Case of Sarcoidosis of Colon

April 2020 • Volume XLIV, Issue 4
Vijeta Pamudurthy,Daniel Errampalli

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CASE PRESENTATION

The patient is a 61-year-old African American female with a history of diabetes mellitus type 2, hypertension, chronic kidney disease stage 4, obstructive sleep apnea, pulmonary sarcoidosis, hyperlipidemia and morbid obesity. She has been on chronic low-dose prednisone for management of pulmonary sarcoidosis. She presented for a screening colonoscopy and had no gastrointestinal symptoms. Colonoscopy revealed moderate diverticulosis of the colon, a 2 mm polyp in the ascending colon (Figure 1), two 2-4mm polyps in the transverse colon and external hemorrhoids.

QUESTIONS

1. What are some differential diagnoses of these polyps?

2. What would a pathology report of sarcoidosis show?

3. What are some possible gastrointestinal manifestations of this lesion?

4. What is the next step in the management of this patient?

DISCUSSION

Question 1.

The different types of colon polyps to consider include:

  • Polyps that arise from submucosa including: lipomas, carcinoids, or lymphoid tissue1
  • Mucosal polyps including:

○ Inflammatory polyps

○ Hamartomatous polyps including juvenile polyps, Peutz-Jeghers polyps, phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome, and Cronkhite-Canada syndrome

○ Serrated polyps including hyperplastic polyps, sessile serrated polyps, traditional serrated adenomas, and serrated polyposis syndrome

○ Adenomatous polyps including tubular, villous, and tubulovillous

Further, there are very rare types of polyps including neurofibromal polyp of the colon and sarcoidosis of the colon. We present a patient with a history of pulmonary sarcoidosis who underwent a screening colonoscopy and was found to have a colon polyp with histology revealing sarcoidosis. Sarcoidosis is a granulomatous disease that causes noncaseating granulomas with multinucleated giant cells.2 Gastrointestinal (GI) involvement is rare and usually occurs subclinically.3

Question 2.

Pathology of the ascending colon polyp revealed nonadenomatous colonic mucosa with nodules of non-necrotizing, “hard,” well formed, noncaseating granulomas and nonspecific chronic inflammation, suggestive of sarcoidosis (Figure 2). There was no histologic evidence of TB, fungal infection, colitis, or foreign body reaction. Remainder of polyps revealed tubular adenomas without highgrade dysplasia.

Question 3.

In a patient with a history of sarcoidosis, it is important to be aware of the various manifestations. Clinically evident GI system involvement occurs in less than 1% of patients with sarcoidosis. Sarcoidosis may present anywhere in the gastrointestinal tract with a multitude of symptoms including obstruction, dysmotility, ulcer, heartburn, nausea, vomiting, pain, and weight loss caused by granulomatous infiltration in the mucosa and muscular layer.4

Question 4.

The optimal treatment for GI involvement is unknown because of the rarity of cases of GI sarcoidosis. Some cases had spontaneous remission and while other cases required glucocorticoid therapy.4 Since our patient did not have any clinical manifestations of gastrointestinal sarcoidosis, she continued on the treatment same dose of glucocorticoid for pulmonary manifestations of the disease.

References

1. Meseeha M, Attia M. Colon Polyps. 2019 Dec 16. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/ NBK430761/ PubMed PMID: 28613512.

2. Levine MS, Ekberg O, Rubesin SE, Gatenby RA. Gastrointestinal sarcoidosis: radiographic findings. AJR Am J Roentgenol. 1989 Aug;153(2):293-5.

3. Friedman M, Ali MA, Borum ML. Gastric sarcoidosis: a case report and review of the literature. South Med J. 2007 Mar;100(3):301-3. Review. PubMed PMID: 17396736.

4. Ungprasert P, Ryu JH, Matteson EL. Clinical Manifestations, Diagnosis, and Treatment of Sarcoidosis. Mayo Clin Proc Innov Qual Outcomes. 2019 Aug 2;3(3):358-375. doi: 10.1016/j. mayocpiqo.2019.04.006. eCollection 2019 Sep. Review. PubMed PMID: 31485575; PubMed Central PMCID: PMC6713839.

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MEDICAL BULLETIN BOARD

U.S. Food and Drug Administration Approves Epclusa for Children with Chronic Hepatitis C Infection

April 2020 • Volume XLIV, Issue 4

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U.S. Food and Drug Administration Approves Epclusa® (Sofosbuvir/Velpatasvir) for Children Ages 6 And Older Or Weighing at Least 17 Kg with Chronic Hepatitis C Infection. Pediatric approval of protease inhibitor-free, pangenotypic, pan-fibrotic, once-daily regimen supports HCV elimination efforts by providing critical option for broad range of populations

Foster City, CA – Gilead Sciences, Inc. (NASDAQ: GILD) announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Epclusa® (sofosbuvir 400mg/velpatasvir 100mg; sofosbuvir 200mg/velpatasvir 50 mg) for the treatment of people with chronic hepatitis C infection (HCV) as young as 6 years of age or weighing at least 17 kg, regardless of HCV genotype or liver disease severity. The recommended dosage of Epclusa in children ages 6 years and older is based on weight and liver function. Epclusa is the first pan-genotypic, protease inhibitor-free regimen approved in the United States for adults and children.

In the United States, there are approximately 23,000-46,000 children living with HCV. Children born to mothers with HCV are a growing concern, increasing in prevalence by 60 percent from 2011 to 2014. Additionally, engagement in high-risk practices, such as intravenous drug use, is an increasingly common route of HCV transmission in adolescents and young adults.

“While the treatment of HCV has been transformed in recent years, physicians caring for some children have still needed to take several factors into consideration, including genotype and liver disease severity, when selecting the appropriate treatment plan,” said Kathleen B. Schwarz, MD, Professor of Pediatrics, Johns Hopkins University School of Medicine. “The expanded approval of Epclusa can help eligible children living with HCV combat this life-threatening and debilitating disease.”

The approval of Epclusa is based on data from a Phase 2, open-label clinical trial (Study 1143) that enrolled 175 children who were treated with Epclusa for 12 weeks, of which 173 were included in the efficacy analysis. In children 12 to <18 years old, treatment with Epclusa resulted in a cure rate (SVR12) of 93 percent (71/76) in those with genotype 1 HCV infection and 100 percent in those with genotype 2 (6/6), genotype3 (12/12), genotype 4 (2/2) and genotype 6 (6/6) HCV infection. In children 6 to <12 years old, the SVR rate was 93 percent (50/54) in those with genotype 1 HCV infection, 91 percent (10/11) in those with genotype 3 HCV infection, and 100 percent in those with genotype 2 (2/2) and genotype 4 (4/4) HCV infection. The safety profile of Epclusa in children 6 years of age and older treated was generally consistent with that observed in clinical trials in adults. The most common adverse reactions (incidence greater than or equal to 10 percent, all grades) observed with treatment with Epclusa for 12 weeks in adults are headache and fatigue.

“Gilead’s continued commitment to HCV elimination includes bringing our medicines to the most difficult-to-cure populations and today’s decision by the FDA represents an important step toward that goal,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “With consistently high cure rates in clinical trials and in the real world, Epclusa has the potential to help many of the children living with HCV in the United States.”

For adults, Epclusa was first approved by the FDA and European Medicines Agency (EMA) in 2016. A line extension application for the use of Epclusa in children 6 to <18 years of age is currently under review with the EMA.

The U.S. product label for Epclusa contains a BOXED WARNING for the risk of hepatitis B reactivation in HCV/HBV co-infected patients. See below for U.S. Important Safety Information.

IMPORTANT U.S. SAFETY INFORMATION AND INDICATION FOR THE USE OF EPCLUSA

BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment followup. Initiate appropriate patient management for HBV infection as clinically indicated.

Contraindications

If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

Warnings and Precautions

Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with EPCLUSA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers and/or Moderate to Potent Inducers of CYP2B6, CYP2C8 or CYP3A4: Rifampin, St. John’s wort and carbamazepine are not recommended for use with EPCLUSA as they may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations.

Adverse Reactions

The most common adverse reactions (≥10%, all grades) with EPCLUSA were headache and fatigue; and when used with RBV in decompensated cirrhotics were fatigue, anemia, nausea, headache, insomnia, and diarrhea.

Drug Interactions

Coadministration is not recommended with topotecan due to increased concentrations of topotecan; or with proton-pump inhibitors, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir.

Consult the full Prescribing Information for EPCLUSA for more information on potentially significant drug interactions, including clinical comments.

INDICATION

EPCLUSA is indicated for the treatment of adult and pediatric patients 6 years of age and older or weighing at least 17 kg with chronic hepatitis C virus genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis.

About Gilead Sciences

Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk that physicians may not see the benefits of prescribing Epclusa for the treatment of chronic HCV infection and the possibility of unfavorable results from ongoing and additional clinical studies involving Epclusa. Further, there is the possibility that the European Commision may not approve the line extension application for the use of Epclusa in the currently anticipated timelines or at all. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2019, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. Prescribing Information for Epclusa, including BOXED WARNING, is available at www.gilead.com.

Epclusa and Gilead are registered trademarks of Gilead Sciences, Inc., or its related companies.

For more information about Gilead, please visit the company’s website at gilead.com, follow Gilead on Twitter (@Gilead Sciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

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Resources for Patients Fighting COVID-19 at Home

March 2020 • Volume XLIV, Issue 3

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From ASPEN’s Website
As Chris Cuomo from CNN shares his battle with the coronavirus — reporting that he lost 13 pounds in 3 days — it’s never more apparent that nutrition and hydration are key weapons in the fight against COVID-19.  

Mr. Cuomo’s struggle is the norm, as only around 12% of patients with COVID-19 are hospitalized.1 Patients managing their illness at home have limited or no guidance on nutrition and hydration management, which are simple but essential weapons for fighting COVID-19.  

With infections, the body must work intensely to mount an immune response; then, work overtime to heal and rebuild damaged tissues. Significant and quick weight loss is due to: a) large fluid losses from the fever, coughing, vomiting and/or diarrhea; and b) muscle breakdown due to the body using protein for energy. The body needs fluid and nutrition to enable it to fight the virus and prevent cannibalizing itself when providing the substrates needed for the fight.  

The American Society for Parenteral and Enteral Nutrition (ASPEN) has created the resources below to help patients optimize their fight against COVID-19. We hope you will share them with your audience. You can find more resources for healthcare professionals at nutritioncare.org/COVID19.
Nutrition and Hydration: Key Weapons in the Fight Against COVID-19. This includes home recipes for a rehydration solution and a high protein shake.
Nutrition and Hydration: Quick Facts for COVID-19 Patients. 

Please feel free to contact me if you have questions.  Sincerely,  Stephanie LeeASPENCommunications Director301-920-9124  1. Razzaghi H, The CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19) — United States, February 12–March 16, 2020. 2020. MMWR Morb Mortal Wkly Rep. 2020;69:343-346.

About ASPEN The American Society for Parenteral and Enteral Nutrition (ASPEN) is dedicated to improving patient care by advancing the science and practice of nutrition support therapy and metabolism. Founded in 1976, ASPEN is an interdisciplinary organization whose members are involved in the provision of clinical nutrition therapies, including parenteral and enteral nutrition. With more than 6,000 members from around the world, ASPEN is a community of dietitians, nurses, nurse practitioners, pharmacists, physicians, scientists, students and other health professionals from every facet of nutrition support clinical practice, research and education. For more information about ASPEN, please visit nutritioncare.org.
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