This section highlights important developments, both of basic science and clinical, published within the past year regarding the stomach and duodenum. Articles and authors were chosen to provide broad-based expert commentary. The following articles have been included: ‘Gastric secretion’ by myself; ‘Gastroduodenal mucosal defense’ by Dr Jonathan Kaunitz; ‘NSAID-induced gastrointestinal and cardiovascular injury’ by Drs Siew Ng and Francis Chan; ‘Helicobacter pylori infection: current clinical areas of contention’ by Dr Peter Malfertheiner; ‘Adverse effects of proton pump inhibitor drugs – clues and conclusions’ by Dr Denis McCarthy; ‘Gastroduodenal motility’ by Drs Jan Tack and Pieter Janssen; ‘Endoscopic management in the bariatric surgical patient’ by Drs Benjamin Levitsky and Wahid Wassef; and ‘Multidisciplinary management of gastric cancer’ by Dr Jaffer Ajani. It is hoped that these reviews will succinctly update and educate researchers and clinicians on recent progress in gastroduodenal physiology, disease, and therapy. I thank the reviewers for their excellent contributions.
Gastric secretion is an intricate and dynamic process regulated by neural, hormonal, and paracrine pathways as well as by mechanical and chemical stimuli. Parietal cells secrete hydrochloric acid as well as transforming growth factor-α, amphiregulin, heparin-binding epidermal growth factor, intrinsic factor, and sonic hedgehog. Much progress has been made toward elucidating the mechanisms and pathways regulating trafficking of the proton pump (H+K+-adenosine triphosphatase; H+K+-ATPase) as well as ion transport within the parietal cell. For acid secretion to occur, there must not only be a functional H+K+-ATPase but also functional apical chloride [cystic fibrosis transmembrane regulator (CFTR)] and potassium (KCNQ1) channels.
To protect themselves from damage by acid and pepsin as well as other noxious substances, the stomach and duodenum utilize a robust and elaborate defense system that includes the microcirculation, epithelial intracellular tight junctions, cellular renewal, inhibition of apoptosis, bicarbonate secretion, mucus secretion, neutralization of reactive oxygen species, innate and adaptive immune responses, phospholipids, trefoil factor peptides, prostaglandins, and heat shock proteins. Lubiprostone, a bicyclic fatty acid derived from prostaglandin E-1, recently approved for treatment of chronic constipation, stimulates bicarbonate secretion via CFTR-dependent and CFTR-independent pathways (e.g., direct activation of EP4 receptors). Although intestinal alkaline phosphatase (IAP) has long been known to be highly expressed in duodenum, its precise function had been unknown. Recent data suggest that IAP acts as a negative feedback chemosensor that inhibits ATP and bicarbonate secretion; and detoxifies lipopolysaccharide by cleaving its phosphate esters.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may be the most important cause of peptic ulcer disease. One-third of NSAID users develop ulcers and 1–2% ulcer complications, with these events more common with long half-life or slow-release formulations. Early resumption of low-dose aspirin at 3–5 days after index ulcer bleed should be strongly considered in patients who require such therapy as early resumption after endoscopic hemostasis reduced all-cause mortality (1 vs. 10%) despite the fact that it increased the risk for recurrent bleeding (10 vs. 5%). A combination of a cyclooxygenase (COX)-2 selective NSAID and a proton pump inhibitor (PPI) provides the best prevention for NSAID-induced gastric lesions. Angiotensin-1 receptor blockers and angiotensin-converting enzyme inhibitors may reduce NSAID-induced ulcers and complications.
Helicobacter pylori (H. pylori) is recognized as a pathogenic factor for the development of gastritis, peptic ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. It has also been implicated in several extragastric disorders, including idiopathic thrombocytopenic purpura and iron deficiency anemia; proof of the latter will require prospective randomized placebo-controlled trials. Current standard triple therapy for H. pylori eradication is facing increased failure rates primarily from antibiotic resistance to clarithromycin and metronidazole. New treatment approaches include sequential therapy, quadruple therapy, and novel regimens substituting either fluoroquinolones or rifamycin for clarithromycin.
Although PPIs are among the most widely prescribed drugs and have an excellent safety record, there has been recent vigorous debate regarding several potential risks, including a drug–drug interaction with clopidogrel, bone fractures, food allergy, infection, and rebound acid secretion. Regarding the potential adverse interaction with clopidogrel (discussed by both Drs Chan and McCarthy), the hypothesis is plausible based upon the fact that cytochrome P450 2C19 (CYP2C19) is the enzyme responsible for metabolizing PPIs, with the possible exception of rabeprazole, as well as converting clopidogrel to its active metabolite. Nevertheless, it should be noted that all clinical outcome studies to date have been retrospective observational studies that cannot determine causation and have not controlled for confounding variables such as cardiovascular risk factors (family history, smoking, hypertension, hyperlipidemia, and obesity), genetic polymorphisms in CYP2C19 (30% whites and 40% blacks) and the fact that the PPI groups contain ‘sicker’ patients with increased prevalence of chronic renal insufficiency and diabetes, both of which increase platelet aggregation and decrease clopidogrel effectiveness; only about half the studies actually show an increase in major adverse cardiovascular events with the combination; and there is no evidence that pantoprazole is devoid of this interaction. Regarding the latter, the study by Juurlink et al. , which is often quoted in support of the notion that pantoprazole is devoid of an interaction with clopidogrel, was, in fact, underpowered as only 46 of the 734 participants were prescribed pantoprazole. Pending resolution of this matter, I suggest that patients taking clopidogrel who require antisecretory prophylaxis receive either rabeprazole or high-dose histamine H2-receptor antagonist; if PPIs are coprescribed, it might be wise to separate the dose of PPI (half-life 1 h) and clopidogrel (half-life 2 h) by 10–12 h. Alternatively, one of the newer antiplatelet agents (e.g., prasugrel, ticagrelor, cangrelor) may be used.
Abnormalities of gastric sensory and motor function play key roles in the pathogenesis of upper gastrointestinal symptoms in functional dyspepsia, gastroparesis, and dumping syndrome. Although emptying of solids is considered the most sensitive and reliable indicator of impaired gastric motor function, recent studies suggest that emptying of liquids is impaired just as frequently as solids in patients suspected of gastroparesis with little overlap between the two tests. The Smartpill, a recently developed nondigestible capsule that records pH, temperature, and pressure, has been shown to be reliable in measuring gastric emptying, small bowel transit, and whole gut transit times. A variety of prokinetic drugs are being developed, including 5-HT4 agonists (e.g., velusetrag), motilin receptor agonists (e.g., GSK962040), and ghrelin agonists (e.g., TZP-101).
Obesity is a global health epidemic and subsequently bariatric surgical procedures [e.g., Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric band (LAGB)] are increasingly performed. The gastroenterologist plays a key role in the preoperative, intraoperative, and postoperative care of these patients. Endoscopy is performed preoperatively to assess for potential disease processes in the distal stomach and proximal small bowel prior to RYGB and for large hiatal hernias prior to LAGB. Intraoperative endoscopy assists the surgeon by assessing staple line hemorrhage, pouch size, stomal diameter, and the integrity of the anastomosis. Surgical complications occur in up to 40% of patients and some of these, such as anastomotic strictures and marginal ulcers, may be managed endoscopically. There is considerable interest in the development of safe and effective endoscopic alternatives to surgery such as endoscopic gastroplasty and endoscopically placed balloons.
Gastric cancer remains common and lethal with overall 10-year survival of approximately 20%. Although early cancers can be cured by surgical resection, most patients in countries where routine screening is not performed, such as the United States, present at more advanced stages. Even when surgery is performed for cure, local and systemic recurrence is common. Unfortunately, adjuvant chemotherapy has failed to show a consistent survival benefit; the same holds true for preoperative chemoradiation. Several new targeted agents show promise such as bevacizumab, cetuximab, and traluzumab.