New Insight Into an Effective Treatment of Marginal Ulceration After Roux-en-Y Gastric Bypass

The endoscopy service at the Brigham and Woman’s Hospital has extensive experience with complications of gastric bypass surgery.¹ Marginal ulceration is one of the most common complications of Roux-en-Y gastric bypass.^2,3 In their practice, all patients with marginal ulcers receive proton pump inhibitor (PPI) therapy, and endoscopy is repeated every 3 months until ulcer healing is confirmed.¹ Some of their clinicians directed patients to open the PPI capsules; others prescribed intact PPIs. The median time for ulcer healing was 3 months in those receiving PPIs emptied from capsules compared with approximately 11 months in those receiving intact capsules. This observation is consistent with the notion that limited absorptive surface and residence time in the absorptive area limited the bioavailability of encapsulated PPIs.

Marginal Ulceration After Gastric Bypass

Limited natural history data regarding post–gastric bypass are available because most centers restrict endoscopy to those with symptoms or complications. Natural history data come from prospective studies by Csendes at al,⁴ who performed endoscopy at 1 month after surgery in 441 post-bypass patients. In 71% of patients, endoscopy was routinely repeated a mean of 17 months after surgery. At 1 month, 5.6% of patients had marginal ulcers (4.1% of those with laparotomy and 12.3% with laparoscopic bypass). Seven ulcer patients (28%) were asymptomatic. At 17 months, 2 patients developed marginal ulcers including one without an early marginal ulcer (0.3%) and one with an early ulcer (4%). A subsequent follow-up of 550 patients included a questionnaire and upper endoscopy done between 1 and 8 years after surgery (mean, 40.5 months). They found 6 patients with marginal ulcers (1%).⁵ All healed with PPI therapy at a mean of 7 months; there was no placebo comparator.

Gastric Bypass

Gastric bypass was originally investigated as a means of treating peptic ulcer disease.^6,7 The operation eliminates the gastrin-related gastric phase of acid secretion because food bypasses the antrum. The empty stomach remains acidic, which caused permanent acid-mediated downregulation of acid secretion, with the small amount of acid produced entering the duodenum. Although gastric bypass was not a successful anti-ulcer operation, it proved effective for treatment of morbid obesity, and bariatric surgery has become one of the most common operations worldwide.

Most marginal ulcers occur within 1 year of surgery. Ulcers that develop soon after surgery have many causes including acid-related as well as related to technical issues such as number of staples, type of suture, presence of tissue traction, or ischemia. Most of the technical difficulties related to pouch size, details of hand-sewn vs stapled anastomoses, and placement of the loop retrocolic or anti-colic have largely been resolved.^8–11 Besides acid from the gastric pouch, dehiscence of the anastomosis between the stomach allows entry of gastric acid causing ulceration that frequently required surgical repair. This problem has become rare because of changes in technique including resection of the remaining stomach. Attempts at preventing ulcers in the early postoperative period by administration of histamine 2-receptor antagonists given as liquids or PPIs even as crushed omeprazole tablets likely reduced the incidence of ulcers but were unable to entirely prevent their development.^12,13 Even today, many surgeons use antisecretory drugs often with sucralfate in the immediate perioperative period.²

Numerous studies have attempted to define patient characteristics associated with an increased marginal ulcer risk (eg, hypertensive, diabetic, Helicobacter pylori infection, use of ulcerogenic medications, smoking, and past peptic ulcer). Most seem less important than acid secretion, and even when acid secretion is not the critical variable, ulcer healing is enhanced by reducing acid secretion (eg, no acid, no ulcer).

The Gastric Pouch and Acid Secretion

The modern gastric pouch is small (ie, typically between 5 and 6 cm in length) with a restricted outlet. After pouch creation, the mucosa remains normal where parietal cells are plentiful and the pouch does not dilate.^14,15 Because the pouch contains a small amount of gastric corpus, the total amount of acid secreted is small.^16,17 However, because parietal cells secrete approximately 150 mmol/L HCl (pH, ~0.8), the intrapouch pH is generally low.^7,18,19 The pouch is vagally innervated; any stimulus to acid secretion is largely restricted to the vagus.⁷ To our knowledge, the effects of vagal stimulation on pouch secretion have not been formally examined. Vagotomy was widely done during the era of surgical treatment of ulcer disease but has been discouraged in gastric bypass.²⁰ Pouch-selective vagotomy is apparently not possible or has not been attempted. At least 1 attempt at transthoracic vagotomy has been reported, but local complications precluded further attempts.²¹

Antisecretory Therapy for Gastric Pouches

PPIs require an acidic compartment in the parietal cell to become activated (ie, only activated parietal cells can be inhibited).²² Traditionally, PPIs are given before meals to allow meal-stimulated gastrin release to activate parietal cells that are then irreversibly inhibited. Full PPI effect takes 3 or more days because not all proton pumps available are inserted into the membrane after meals.²² As noted, gastric bypass prevents meal-stimulated activation of parietal cells. Alert clinicians at Brigham and Woman’s Hospital thought that breaking the PPI capsules open would likely increase the bioavailability of PPIs. The barriers to bioavailability include capsule dissolution and release of the enteric-coated granules of PPI, which must then dissolve, and all of this must occur within the short length of intestine available. However, improved absorptivity does not solve the need to activate parietal cells during the short time the PPI is in the plasma.

How To Best Deliver and Access Antisecretory Drug Therapy?

The effectiveness of increasing PPI bioavailability could be assessed by measuring plasma PPI levels (absorption) or by assessing reduction in acid secretion directly or indirectly such as by changes in intrapouch pH. There is a considerable and detailed literature on the preparations of PPIs including granule dissolution for related conditions.^23,24 We believe the easiest approach would be to administer non–enteric-coated PPI powder with sodium bicarbonate, which is rapidly absorbed and available commercially with 20 or 40 mg omeprazole.

Because antral exclusion makes it difficult to activate parietal cells and the plasma half-life of a PPI is very short, it would seem likely that 2 or 3 times a day dosing, possibly of smaller amounts, would be most effective.²⁵ The best approach to assess effectiveness would likely be to compare the time the intrapouch pH remained greater than 4 after about 5–7 days of PPI therapy. When it becomes available, vonoprazan is likely to be superior to traditional PPIs in that activation of the parietal cell is not needed. Histamine 2-receptor antagonists are another option, although they are less effective in maintaining the intragastric pH above 4.

Summary

The clinicians at Brigham and Woman’s Hospital are to be congratulated for showing that it is possible to reduce the healing time of post Roux-en-Y gastric-associated marginal ulcers. Many questions remain to be answered to understand and optimize the use of PPIs for marginal ulcers. These studies should be easy to perform, and we anticipate rapid further progress.