Novel upper gastrointestinal developments prof. Peter Malfertheiner – Gastro Update Europe 2019, Budapest

Gastroesophageal reflux disease (GERD) may well be further increasing as Helicobacter Pylori infection risk continues to fall. Pathophysiological concepts, summarized in the figure below remain essentially unchanged but there is increasing interest in the concomitant role of functional dyspepsia with mucosal gastro-duodenal inflammation, delayed gastric emptying and impaired gastric accommodation, all favouring transient sphincter relaxations, together with enhanced sensitivity.

Hypersensitivity appears, in part, related to altered afferent signalling and aberrant sensory characteristics. Whereas infusion of menthol in the esophagus evoked a mild cold sensation in healthy subjects, this was perceived as rather painful heartburn in GERD patients. Refractoriness to proton pump inhibition (PPI) (esomeprazole 40 mg/day (d) /8 weeks) remains a challenging problem and deserves prolonged multichannel impendence-pH investigation. As shown in an Italian study, only one third of such patients had non-erosive reflux disease (+ acid exposure time and + symptom association probability), the others suffered from reflux hypersensitivity (normal acid exposure time) or from functional heartburn. For those true non-responders, more profound acid suppression with a potassium-competitive acid blocker (pCAB) would be an option. The mechanism of action of P-CABs differs from that of PPIs (Fig. 1 and 2). A recent Japanese study in PPI-refractory patients showed normalisation of esophageal acid exposure in 46%, together with symptom improvement and healing of esophagitis with 20 mg/d vonoprazan. For the time being P-CABs are not (yet) available in Europe.

Regurgitation, particularly when severe, may also be refractory even to high-dose PPI therapy and calls for other approaches, such as endoscopic fundoplication, magnetic sphincter augmentation or standard antireflux surgery.

Esophageal columnar metaplasia (Barrett) continues to raise major clinical interest and controversy. Whether all patients with Barrett esophagus, also those that are asymptomatic should enter a surveillance program to detect early neoplasia is not answered in a uniform way in the currently existing guidelines. It is also somewhat controversial whether acid suppression with PPIs decrease the cancer risk because PPIs are commonly prescribed for reduction of heartburn symptoms. In support of non-stop acid suppression was a recent nested case-control study in 300 American veterans showing a 41% reduction in esophageal adenocarcinoma in PPI users. Can chemoprevention be further improved by combining PPIs with aspirin? The long-awaited results of the large British AspECT chemoprevention study, which randomized 2,557 patients to low-dose (20 mg/d) or high-dose (40 mg × 2/d) esomeprazole with or without 300 mg aspirin/d, followed for a median 8.9 years, were recently published. High-dose PPI was superior to low-dose PPI in delaying the combined end point of (all-cause mortality, high-grade dysplasia or adenocarcinoma). Aspirin was not significantly associated with a decreased risk of the combined outcome. It would appear that the benefit of the study was largely related to a reduction of all-cause mortality. What does this all mean for clinicians? For the time being clinicians should try to stratify patients in a low or high risk category using the common clinical/endoscopic characteristics. Low risk patients should be advised to stop smoking, moderate the diet and receive chemoprevention with (high-dose) PPI and aspirin. High risk patients should enter an endoscopic surveillance program and be treated whenever dysplastic/neoplastic changes develop with endoscopic resection and/or radiofrequency ablation or other alternative modalities. Remember that it is not unusual that only about half of the clinicians adhere to established guidelines.

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization and even death. It was estimated that 30% of American elderly consumed 5–9 pills/d. PPIs, of which the consumption is still rising, were often included. When correctly prescribed PPIs play an essential therapeutic role in medicine. A recent high-quality systematic review and meta-analysis demonstrated the substantial benefits of PPI treatment. Over 140,000 patients were analysed in 580 prevention trials, 233 healing trials and 36 bleeding trials. Compared to controls and other gastroprotectants, PPIs were overall 5× more effective in reducing risk and 5× more effective in tissue improvement/healing. This glamorous result needs to be balanced with the negative consequences of long-term PPI induced acid suppression, particularly when related to enhanced esophageal and gastric cancer risk as discussed in last year’s highlight. Despite all critical comments and study shortcomings, it would seem sensible to add neoplasia to well-known list of adverse events (Fig. 3).

The enhanced gastric cancer risk of long-term acid suppression may well be related in part to gastric dysbiosis and perhaps to chronically elevated gastrin levels. Interestingly, in one study the enhanced risk was only seen in those individuals who were not taking additional Aspirin. Clinicians should be aware of the above-mentioned association studies, while realising that randomized controlled trials are impossible and that association studies are always prone to known and unknown confounders. Anyhow, the main message of all these studies is that chronic profound (PPI-induced) acid suppressant therapy should only be prescribed for the proper indications, realising that a very substantial percentage of PPI prescriptions, also in the elderly, are inappropriate.

Eosinophilic esophagitis prevalence is rising also in the Far East, becoming the leading cause of esophageal food impaction in children and young adults. The prevalence calculated in 24 studies is now approx. 34/100,000 cases. Note that a proper diagnosis does no longer require disease resistance to PPI therapy, as up to 60% of genuine eosinophilic esophagitis patients respond to PPIs, presumably based at least in part upon their anti-inflammatory activity. The terminology of PPI-responsive esophageal eosinophilia should therefore be omitted in clinical practice. The updated international consensus diagnostic criteria for eosinophilic esophagitis includes:

• symptoms of esophageal dysfunction;
• at least 15 eosinophils per high-power field (approx. 60/mm²);
• comprehensive exclusion of other disorders that could contribute to esophageal eosinophilia.

According to a systematic review, H. Pylori exposure was associated with a 37% reduction in the risk of eosinophilic esophagitis. This finding fits with the observation that exposure to H. Pylori early in life skews immune responsiveness more in the T helper 1 direction than in the pro-allergy T helper 2 direction. Medical therapy usually starts with PPIs, followed by corticosteroids if PPIs fail. A recent 8 week controlled trial comparing oral viscous budesonide with fluticasone inhalation revealed equal reduction in mucosal eosinophilia and improvement in dysphagia. Two important drivers of eosinophilic activation are interleukines (IL) IL-5 and IL-13. A monoclonal antibody targeting IL-5 has already been shown to be efficacious. Novel is the experimental evaluation of a monoclonal antibody against IL-13 which was also shown to be efficacious in reducing esophageal eosinophilia and in reducing symptomatology, deserving further evaluation. Not discussed at the meeting but important to mention is the renewed interest in empiric elimination diet to decrease the allergenic load. It all started with the step-down six-food elimination diet, followed by 4-food and the 2-food elimination diet (the 6-4-2 system) with the gradual re-introduction of nutrients, a costly time-consuming laborious procedure. A more rational, patient-friendlier approach, decreasing the endoscopic burden, was launched in Spain, the (2-4-6) step-up protocol, thus starting with the 2-food (milk, wheat) elimination diet (which was effective in approx. 40%, the majority related to avoidance of milk or dairy) with sequential elimination of other food items. Ultimately, there will be a sequence of eliminations: dairy, + wheat, + egg, + soy/legumes, + nuts, seafood, + beef/corn. In practice, successful dietary therapy demands substantial patient education, engagement and motivation to adhere to the elimination diet.

It is common knowledge that H. Pylori infection is associated with multiple gastroduodenal and extra-intestinal manifestations. In a recent important meta-analysis the role of H. Pylori infection was evaluated in low-dose Aspirin users. In infected individuals, the risk of Aspirin-induced ulceration rose by almost 70% and in the absence of protective acid suppressants, by almost 100%. Low-dose Aspririn, variably defined in the literature is not innocent therapy. I wonder to what extent chronic low-dose Aspirin may be related to the common anemia seen in the elerly.

Most of the information of H. Pylori eradication in the prevention of gastric cancer was generated in the Far East. Now, also data from a western population became available. A population based cohort of over 95,000 individuals with eradication of the infection was followed; overall 0.1% developed gastric cancer. The risk decreased gradually with incidence ratios of 8.6 after 3–5 years and 0.3 after 5–7.5 years of follow-up, confirming the gradual suppression of gastric cancer development. Similar results were seen in asymptomatic individuals from a health screening program; compared to controls the risk of gastric cancer expressed as hazard ratio was 4.12 and dropped to 2.73 in those after H. Pylori eradication. One may readily assume that such cancer protective effect is related to the gradual improvement of atrophic gastritis and even (partial) reversibility of intestinal metaplasia after eradication of the infection. Such phenomenon may also explain the prevention of metachronous gastric cancer shown in a randomized trial of 470 patients after endoscopic removal of early gastric cancer. Metachronous cancer developed in 7% in the eradiation group vs. 13% in the placebo group, again paralleled by improvement in atrophy in respectively 48 vs. 15%. Despite some recent publications from the western world, it is still unclear whether population screening for H. Pylori infection and serologic screening for pre-neoplastic gastric mucosal atrophy/metaplasia is warranted. Should serologic screening be encouraged in combination with screening for colorectal neoplasia in individuals above 59 years of age in western societies that have low or intermediate risk of gastric cancer? Should fecal occult blood screening be combined with stool H. Pylori antigen screening?

The drama with the rising antimicrobial resistance, particularly for clarithromycin, metronidazole and levofloxacin continues. Successful therapies for infectious diseases should ideally be susceptibility-based but this involves extra costs and effort compared to empiric therapies. This dilemma was recently studied in a controlled trial involving 382 patients, randomized to 14 d empiric quadruple therapy (esomeprazole, bismuth, amoxicillin, metronidazole) vs. susceptibility-guided therapy, with respective eradication rates per protocol of 97.6 vs. 97.7% and per intention-to-treat of 85.4 vs. 91.6%, a non-significant difference. It remains difficult to recommend susceptibility-based treatment for first-line therapy in clinical practice until such therapy is proven to be superior and cost-effective. Perhaps all this will change if the initial remarkable eradication results with 14 d dual therapy with high-dose esomeprazole and amoxicillin can be reproduced in other cohorts in the west. The results mirror the high eradication also obtained with dual therapy with the pCAB vonoprazan and amoxicillin. It would certainly be progress if such dual therapy would be effective because resistance to amoxicillin is almost negligable – the only problem would be penicillin allergy.

The Gastro Update Europe 2020 will be held on June 5–6, 2020 in Bratislava, Slovakia. For more information visit www.gastro-update-europe.eu.

Prof. Guido Tytgat, MD, PhD

Department of Gastroenterology and Hepatology

Academic Medical Center

Meibergdreef 9

1105 AZ Amsterdam

The Netherlands

 g.n.tytgat@amc.uva.nl