Key points

Introduction

The introduction of acid suppressants and the recognition of Helicobacter pylori as a pathogen revolutionized gastroenterology practice. It meant that chronic, debilitating conditions, such as peptic ulcer disease, could be treated with a course of antibiotics. Patients were relieved from the stigma of suffering from a psychosomatic disease and from long treatments and hospital admissions, often ending in surgery. A younger generation of physicians may easily underestimate this impact. The author and colleagues previously estimated it for the Netherlands alone, a small country with 17 million inhabitants. The improvement in peptic ulcer treatment led to a yearly gain of 46,000 quality-adjusted life-years and annual savings of at least €1.8 billion. These major changes have not removed the necessity for endoscopic follow-up for a proportion of patients with H pylori –associated conditions. They need follow-up to monitor the underlying disease and/or to confirm successful bacterial eradication when persistent colonization puts patients at significant risk for disease recurrence or progression. This article focuses on the need for endoscopic follow-up after H pylori eradication therapy ( Table 1 ).

Introduction

The introduction of acid suppressants and the recognition of Helicobacter pylori as a pathogen revolutionized gastroenterology practice. It meant that chronic, debilitating conditions, such as peptic ulcer disease, could be treated with a course of antibiotics. Patients were relieved from the stigma of suffering from a psychosomatic disease and from long treatments and hospital admissions, often ending in surgery. A younger generation of physicians may easily underestimate this impact. The author and colleagues previously estimated it for the Netherlands alone, a small country with 17 million inhabitants. The improvement in peptic ulcer treatment led to a yearly gain of 46,000 quality-adjusted life-years and annual savings of at least €1.8 billion. These major changes have not removed the necessity for endoscopic follow-up for a proportion of patients with H pylori –associated conditions. They need follow-up to monitor the underlying disease and/or to confirm successful bacterial eradication when persistent colonization puts patients at significant risk for disease recurrence or progression. This article focuses on the need for endoscopic follow-up after H pylori eradication therapy ( Table 1 ).

Helicobacter pylori eradication

The first antimicrobial therapy for intragastric flagellated bacilli was introduced more than 100 years ago. This treatment in particular consisted of high doses of bismuth, often for prolonged periods. Soon after the first culture of H pylori , attempts were made to eradicate this bacterium. For that purpose, bismuth therapy was combined with other antimicrobials. Since those first successful attempts, the success rates of eradication therapy plateaued. Other drugs, such as proton pump inhibitors and a range of antimicrobials, were introduced in various combinations. Many combinations of a proton pump inhibitor with 1 to 3 antimicrobials as well as 3 to 4 antimicrobials including bismuth were applied over the years. These drugs were all given together or in sequential combinations. Many of these combinations first yielded promising eradication results. Unfortunately, further studies and use in daily clinical practice without exception showed limitations. These limitations were among others caused by the rapid increase of antimicrobial resistance in H pylori . More complex regimens, such as the combination of 4 drugs, prolonged treatment, and sequential regimens often also decrease adherence, among others, because of side effects. This factor explains that, in many daily clinical practice settings, 15% to 40% of eradication attempts fail. This failure rate explains the need to assess the outcome of eradication treatment in some patients. Most of these patients do not need endoscopic follow-up. Their H pylori status can, thus, be reassessed noninvasively. Urea breath tests, fecal antigen tests, and conventional serology serve this purpose. Serology is, in most settings, not convenient because it needs a long time interval between treatment and reassessment. Urea breath tests are excellent for this purpose. They are highly accurate; patient burden is minimal; and costs are low. However, they are not always available. In practices where none of these noninvasive options are available, renewed endoscopy may be required to reassess H pylori status. This situation is preferentially avoided, both because of the patient burden and costs. Against this background, endoscopic follow-up after H pylori eradication pertains to the following situation.

Uninvestigated and nonulcer dyspepsia

H pylori colonization and dyspepsia are both common phenomena, which explains the considerable overlap between the two (ie, a considerable proportion of patients with dyspeptic symptoms are H pylori positive). The causal relation between the two is, however, limited. The effect of H pylori eradication on nonulcer dyspepsia is, thus, also small. More than 15 prospective randomized controlled trials compared the effect of H pylori eradication with placebo in patients with nonulcer dyspepsia. On average, the number needed to treat to cure one patient with dyspepsia was 14. It often took 6 to 12 months for symptoms to improve.

This finding implies that patients who receive H pylori eradication therapy for nonulcer dyspepsia first need adequate explanation that the effect on symptoms is not guaranteed and may take months. If a patient reports after 6 to 12 months of follow-up with persistent or recurrent symptoms, H pylori status may be reassessed. This reassessment will preferably be done by a noninvasive test. Endoscopy needs to be considered if noninvasive tests are not available.

A related category consists of patients who have received H pylori eradication after noninvasive testing only, without endoscopy. This category of uninvestigated dyspepsia includes patients with nonulcer dyspepsia as well as patients with other conditions, such as peptic ulcer. Patients with uninvestigated dyspepsia who report with persistent or recurrent symptoms after H pylori eradication are eligible for endoscopy. This eligibility allows reassessing H pylori status as well as evaluating the presence of specific disease, such as peptic ulcer.

Peptic ulcer

H pylori and nonsteroidal antiinflammatory drugs (NSAIDs) in most settings cause more than 90% of peptic ulcers. The remainder is caused by a range of other causes, including other microorganisms, other drugs, and cancer. H pylori and NSAIDs interact in the etiology of ulcers; the risk for peptic ulcer is higher in an H pylori –positive NSAID user than in patients with either factor alone. It is estimated that the lifetime risk for the development of peptic ulcer in the presence of H pylori lies in the order of 20%. Once an individual develops an H pylori –associated peptic ulcer, he or she is at a more than 50% risk of recurrent ulcer disease within the next 24 months. This risk explains that peptic ulcer used to be a chronic, recurrent disease. Acid-suppressive maintenance therapy reduces the recurrence rate but does not prevent recurrent peptic ulcer. H pylori eradication leads to an almost complete cure of chronic recurrent ulcer disease. For that reason, H pylori eradication is the mainstay of treatment of peptic ulcers associated with H pylori colonization. Eradication treatment is similarly important in H pylori -positive patients with peptic ulcer and simultaneous of aspirin or NSAIDs. Ulcer recurrence rates after eradication treatment are very low. Ulcers can reoccur in patients with recrudescent or renewed infection or patients taking ulcerogenic drugs, in particular NSAIDs or aspirin. Against this background, patients with uncomplicated duodenal disease do not require endoscopic follow-up or routine reassessment of their H pylori status after eradication treatment. In case of recurrent or persistent symptoms, the effect of eradication treatment needs to be assessed at least 4 weeks after treatment. This reassessment is preferentially done noninvasively, for instance, by means of urea breath testing. This approach does not pertain to all peptic ulcers. Two exceptions are gastric ulcer disease and complicated peptic ulcer.

Gastric ulcer disease can be caused by an underlying malignancy. This underlying malignancy includes adenocarcinoma, lymphoma, other primary gastric malignancies, as well as metastatic disease. This factor implies that assessment for the underlying cause not only requires assessment of H pylori status and drug use but also requires biopsy sampling from the ulcer rim itself. If this demonstrates an underlying malignancy, management first fully aims at cancer treatment. H pylori eradication only has a role during follow-up in those patients in whom (part of) the stomach is preserved (see later discussion). In patients with a gastric ulcer without histologic signs of malignancy, H pylori eradication is again the first treatment. However, because a single round of biopsy sampling may miss cancer, a follow-up endoscopy 1 month after the end of eradication treatment may be considered. This practice allows both to assess the effect of eradication treatment and to obtain additional ulcer histology to further exclude cancer. The yield of such surveillance is limited. Most studies date from the era of fiberoptic endoscopy or the early times of video endoscopy. They suggested a 2% to 5% cancer miss rate with initial endoscopy. With these old roots, the practice of endoscopic surveillance for gastric ulcer is, nevertheless, still quite widely practiced. In a US survey among 6113 patients with gastric ulcers, 25% underwent surveillance endoscopy. Current image-enhanced endoscopy techniques, such as narrow-band imaging, allow detailed assessment of the ulcer surroundings and targeted biopsies of visible lesions. This assessment likely enhances the yield of biopsy sampling and, thus, reduces the risk that any underlying malignancy is overseen. With this modern equipment, endoscopists may well consider to refrain from endoscopic surveillance in patients with negative histology and regular/benign-appearing ulcer with evident cause (in particular H pylori or NSAID use). Patients with initial negative histology, but irregular ulcer, no defined cause, and/or persistent symptoms should be considered for surveillance endoscopy with repeat biopsy sampling.

A second group of patients with peptic ulcers for whom endoscopic follow-up is recommended after H pylori eradication consists of those with complicated peptic ulcer. The most common complication is ulcer hemorrhage, followed by perforation and gastric outlet stenosis. Peptic ulcer bleeding is a severe complication associated with significant morbidity and mortality. Endoscopic therapy forms the mainstay of diagnosis and treatment. This therapy can be done by injection therapy, coagulation, or clipping. Although epinephrine injection may initially stop the bleed, it is insufficient as monotherapy for the treatment of bleeding peptic ulcer. It should, therefore, be combined with other modalities. Patients who show, during endoscopy, active bleeding or stigmata of recent hemorrhage, in particular a visible vessel, should, after adequate endoscopic treatment, receive high-dose intravenous proton pump inhibitors. After the acute phase, patients need to be assessed for the presence of H pylori and, if positive, receive eradication treatment. In a systematic review of 7 studies with 578 patients with bleeding peptic ulcer, rebleeding occurred in 3% after H pylori eradication versus 20% after acid-suppressive therapy alone. The same approach pertains to patients with a perforated ulcer, for whom the initial treatment usually consists of surgical closure of the perforation. In a randomized trial comparing H pylori eradication versus 4 weeks omeprazole treatment of perforated peptic ulcer, recurrent ulcer occurred in 5% after eradication treatment versus 38% after omeprazole. For patients with gastric outlet stenosis, the initial treatment may consist of balloon dilation, or sometimes surgery, followed by H pylori eradication if H pylori positive. Because the risk of renewed complicated ulcer disease in any of these patients groups (bleeding, perforation, stenosis) is considerable, it is mandatory to assess H pylori status after eradication treatment. These patients will usually be kept on proton pump inhibitor therapy until confirmation of successful H pylori eradication. This therapy may affect the accuracy of urea breath testing, particularly the increase in the rate of false negatives. For that reason, follow-up of patients with previous complicated peptic ulcer is primarily done by endoscopy with renewed biopsy sampling from antrum and corpus to reassess H pylori status. Once H pylori eradication has been confirmed, further acid-suppressive therapy can be stopped because the risk of recurrent ulcer in the absence of H pylori and the risk for reinfection are both very low. However, if a patient with a history or complicated peptic ulcer has a strong need for NSAID/aspirin use without alternative options, gastroprotection by means of acid suppressive therapy is again needed.