Frontiers in functional dyspepsia

Functional dyspepsia (FD) refers to unexplained pain or discomfort in the upper abdomen and is commonly seen in gastroenterology practice. The underlying pathophysiologic mechanisms associated with FD are unclear, although traditionally, delayed gastric emptying, visceral hypersensitivity to acid or mechanical distention, and impaired gastric accommodation have been implicated as putative physiologic disturbances. It also remains uncertain whether FD and irritable bowel syndrome are different presentations of the same disorder. Recent data on pathophysiologic mechanisms of FD have focused on postprandial motor disturbances (accelerated gastric emptying, antral-fundic incoordination, and abnormal phasic contractions), alterations of neurohormonal mechanisms in response to a meal, and previous acute infection. Pharmacologic therapies for FD may be guided by these novel mechanisms, as current available therapeutic options are limited. Novel prokinetics and gastric accommodation modulators, visceral analgesics, and agents targeting the neurohormonal response to food ingestion are the next therapeutic frontiers in FD. This review summarizes traditional knowledge and more recent advances in the pathophysiology of FD and potential therapeutic opportunities.     

Treatment of functional dyspepsia

Opinion statement Functional dyspepsia (FD) is a common reason a patient presents with upper gastrointestinal symptoms for medical care. Although treatment of FD remains expensive, the agents are rarely used in a systematic manner; the majority of treatments are empirical and the results short lived once therapy is ceased. This is partly due to the lack of consistent pathophysiologic markers in FD, so therapy is symptom driven. This review appraises the best evidence on available interventions. A structured scheme for deciding on appropriate therapies is to consider the possible putative pathophysiologic mechanisms. Eradicating Helicobacter pylori, if present, is a first-line strategy. In patients who have symptoms suggesting excessive gastric acid secretion, particularly epigastric pain, antisecretory agents are recommended. Prokinetics may confer benefits on symptoms suggestive of upper gastrointestinal dysmotility, like fullness or early satiety. However, their use is limited due to availability issues. The expanding field of psychologic therapies provides a promising avenue of treatment. Complementary medicines are now widely use and their benefits have been suggested in recent controlled trials. Emerging treatments include cholecystokinin 1 blockers, opioid receptor agonists, and serotonergic agents, although their application in FD is in the preliminary stages.     

Pathogenesis and therapy for idiopathic dyspepsia

Functional dyspepsia (FD) is one of the most common gastrointestinal disorders. This review summarizes recent progress in our understanding of the pathogenesis and therapy for FD. Although distinction among FD, irritable bowel syndrome, and reflux disease is difficult in population-based studies, separate entities can be recognized in patients who seek medical attention. The pathogenesis of FD remains unclear, but recent studies have demonstrated a role for acute gastrointestinal infection in triggering FD and in genetic polymorphisms of G-proteins in predisposing to FD. The role of abnormalities in gastric motor function, visceral hypersensitivity, and psychosocial factors in the pathophysiology of dyspeptic symptoms has been the topic of multiple studies. Treatment options for FD remain limited. Recent studies have focused on acid-suppressive drugs and on novel prokinetics. Progress in our understanding of the pathogenesis and pathophysiology of FD may lead to new or improved treatment modalities. Areas of major advances are the role of infection and genetic predisposition and studies on the role of abnormalities in gastric motility and sensitivity.     

Therapeutic strategies for functional dyspepsia and the introduction of the Rome III classification

Although placebo response rates in clinical trials for functional dyspepsia (FD) are more than 30%, a recent meta-analysis based on randomized controlled trials (RCTs) showed that antisecretory drugs were more or less superior to placebos. On the other hand, large-scale RCTs on the efficacy of treatment with prokinetics on FD are still needed. Indications for antibiotic eradication therapy for Helicobacter pylori-positive FD are still controversial, but there seems to be a small but significant therapeutic gain achieved with H. pylori eradication. Since preprandial and postprandial symptomatic disturbances are very important targets for FD treatment, ghrelin, a novel appetite-promoting gastrointestinal peptide that also promotes gastric motility or basal acid secretion can be expected to be a therapeutic target. In the recently published Rome III classification, FD is redefined for patients with symptoms thought to originate from the gastroduodenal region, specifically epigastric pain or burning, postprandial fullness, or early satiation, and it is divided into the subcategories postprandial distress syndrome and epigastric pain syndrome. These new criteria are of value in clinical practice, for epidemiological, pathophysiological, and clinical research, and for the development of new therapeutic strategies.     

Functional dyspepsia: New insights into the pathophysiology

Abstract The pathogenesis of functional dyspepsia remains poorly understood. There is increasing evidence pointing to a predominant role of gastroduodenal visceral hypersensitivity in the pathogenesis, where patients have abnormally reduced gastric and small intestinal sensory thresholds. Motor abnormalities observed in subgroups of patients include delayed gastric emptying, antral hypomotility, gastric dysrhythmias, abnormal gastrointestinal reflexes and small intestinal dysmotility, but these may be secondary pheno nena. The central nervous system modifies peripheral visceral afferent pathways and, hente, psychological factors may possibly alter symptom status. Other putative mechanisms include Helicobacter pylori gastritis and gastric acid hypersecretion or sensitivity, but the role of these remain controversial.     

Gastric Emptying is Altered with the Presence of Gastritis

Helicobacter pylori infection and gastritis can cause symptoms suggestive of altered gastrointestinal function; however, it is unclear if H. pylori influences gastric motility. This study assessed gastric emptying rates in mouse models of gastritis. Gastritis was induced in C57BL/6 mice via ethanol treatment or via challenge with H. pylori or H. felis. Gastric emptying rates of nutrient and non-nutrient liquids were assessed with the non-invasive ¹³C-breath test, and the results were compared to healthy mice. Gastric emptying of the non-nutrient liquid was unaltered with the presence of gastritis; however, gastric emptying of the nutrient liquid was accelerated after a 4-week infection with H. pylori. H. felis infection and ethanol treatment caused a more severe gastritis and disruptions to the normal gastric emptying. Changes to gastric emptying in mouse models of gastritis are associated with the presence of nutrients. Altered gastric emptying may contribute to symptoms commonly reported in humans with gastritis.     

Gastrointestinal hormone abnormalities and G and D cells in functional dyspepsia patients with gastric dysmotility

AIM: To investigate the relationship between gastric dysmotility, gastrointestinal hormone abnormalities, and neuroendocrine cells in gastrointestinal mucosa in patients with functional dyspepsia (FD). METHODS: Gastric emptying was assessed with solid radiopaque markers in 54 FD patients, and the patients were divided into two groups according to the results, one with delayed gastric emptying and the other with normal gastric emptying. Seventeen healthy volunteers acted as normal controls. Fasting and postprandial plasma levels and gastroduodenal mucosal levels of gastrointestinal hormones gastrin, somatostatin (SS) and neurotensin (NT) were measured by radioimmunoassay in all the subjects. G cells (gastrin-producing cells) and D cells (SS-producing cells) in gastric antral mucosa were immunostained with rabbit anti-gastrin polyclonal antibody and rabbit anti-SS polyclonal antibody, respectively, and analyzed quantitatively by computerized image analysis. RESULTS: The postprandial plasma gastrin levels, the fasting and postprandial plasma levels and the gastric and duodenal mucosal levels of NT were significantly higher in the FD patients with delayed gastric emptying than in those with normal gastric emptying and normal controls. The number and gray value of G and D cells and the G cell/D cell number ratio did not differ significantly between normal controls and the FD patients with or without delayed gastric emptying. CONCLUSION: Our findings suggest that the abnormalities of gastrin and NT may play a role in the pathophysiology of gastric dysmotility in FD patients, and the abnormality of postprandial plasma gastrin levels in FD patients with delayed gastric emptying is not related to the changes both in the number and gray value of G cells and in the G cell/D cell number ratio in gastric antral mucosa.     

A case of isolated granulomatous gastritis that spontaneously resolved without Helicobacter pylori eradication

Isolated or idiopathic granulomatous gastritis (IGG) is a rare disease and its etiology remains unclear. Some recent papers have reported that IGG is caused by Helicobacter pylori. We present herein a case of IGG that resolved spontaneously without H. pylori eradication. A 54-year-old woman displayed rigidity and thickened folds in the gastric corpus on upper gastrointestinal series. Upper gastrointestinal endoscopy revealed erythematic mucosa and thickened folds. Biopsies of gastric mucosa taken via endoscopy showed noncaseating granulomas and H. pylori infection. The patient was diagnosed with IGG, as no causes of granuloma (e.g., Crohn’s disease, sarcoidosis, foreign bodies), excluding H. pylori were identified. Since this patient did not have any symptoms, she was followed without medication, including for eradication of H. pylori. Rigidity and thickened folds normalized with 6 months. Although H. pylori is suspected as the cause of IGG, this case resolved without H. pylori eradication. We thus conclude that the cause of IGG is not H. pylori alone.     

The possible role of gastrointestinal endocrine cells in the pathophysiology of irritable bowel syndrome

Introduction: The etiology of irritable bowel syndrome (IBS) is unknown, but several factors appear to play a role in its pathophysiology, including abnormalities of the gastrointestinal endocrine cells. The present review illuminates the possible role of gastrointestinal hormones in the pathophysiology of IBS and the possibility of utilizing the current knowledge in treating the disease.

Areas covered: Research into the intestinal endocrine cells and their possible role in the pathophysiology of IBS is discussed. Furthermore, the mechanisms underlying the abnormalities in the gastrointestinal endocrine cells in IBS patients are revealed.

Expert commentary: The abnormalities observed in the gastrointestinal endocrine cells in IBS patients explains their visceral hypersensitivity, gastrointestinal dysmotility, and abnormal intestinal secretion, as well as the interchangeability of symptoms over time. Clarifying the role of the intestinal stem cells in the pathophysiology of IBS may lead to new treatment methods for IBS.     

Functional dyspepsia: recent pathophysiological advances

Functional dyspepsia is a clinical syndrome defined by upper abdominal symptoms, without identifiable cause by conventional diagnostic evaluation. New diagnostic tests, such as gastrointestinal manometry and gastric emptying, may help in a better characterization of these patients by demonstrating specific motor abnormalities, such as postprandial antral hypomotility and delayed gastric emptying of solids, or less frequently, intestinal dysmotility patterns indicating a visceral neuropathy. Nevertheless, a substantial proportion of dyspeptic patients have normal motility patterns. Interestingly, recent studies have shown that a gastric hypersensitivity to distension may be the cause of the postprandial symptoms in functional dyspepsia. These data indicate that functional dyspepsia may include an heterogeneous group of patients with different underlying disturbances.     

功能性消化不良的中医治疗概况

功能性消化不良(functional dyspepsia,FD)是常见的功能性胃肠病之一,临床表现包括上腹疼痛、早饱、餐后不适、上腹烧灼感等。目前FD的诊断主要以功能性胃肠病罗马Ⅳ标准为依据,分为餐后不适综合征(postprandial discomfort syndrome,PDS),上腹痛综合征(epigastric pain syndrome,EPS)以及二者的重叠3个亚型[1]。有研究显示,全球FD的发病率为10%~30%[2]。     

Functional dyspepsia： The role of visceral hypersensitivity in its pathogenesis

Functional, or non-ulcer, dyspepsia (FD) is one of the most common reasons for referral to gastroenterologists. It is associated with significant morbidity and impaired quality of life. Many authorities believe that functional dyspepsia and irritable bowel syndrome represent part of the spectrum of the same disease process. The pathophysiology of FD remains unclear but several theories have been proposed including visceral hypersensitivity, gastric motor dysfunction, Helicobacter pylori infection and psychosocial factors. In this review, we look at the evidence, to date, for the role of visceral hypersensitivity in the aetiology of FD.     

Postprandial distress syndrome: stratification and management

Introduction: Functional dyspepsia (FD), defined by the Rome consensus as the presence of functional symptoms originating from the gastroduodenum, is one of the most common functional gastrointestinal disorders. FD is subdivided into postprandial distress syndrome (PDS), with meal-related symptoms such as postprandial fullness and early satiation, and epigastric pain syndrome (EPS), with meal-unrelated symptoms such as epigastric pain or burning. We used a literature search for a narrative review on the current state of knowledge regarding PDS.

Areas covered: Epidemiological studies support PDS as a separate entity and the biggest FD subgroup. The pathophysiology of PDS is heterogeneous, and disorders of gastric sensorimotor function as well as low grade duodenal inflammation have been implicated. Although prokinetic agents may provide the most pathophysiology-oriented treatment option, there is a paucity of suitable agents, and proton pump inhibitors are the traditional first-line therapy. Other options include agents that enhance gastric accommodation, such as acotiamide and 5-HT_1A agonists, neuromodulators such as mirtazapine, and traditional medicine approaches.

Expert commentary: PDS is highly prevalent, with probably heterogeneous underlying pathophysiology. Motility modifying agents and neuromodulators are the cornerstone of PDS therapy, but there is a need for high quality studies of new therapeutic approaches.     

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

Functional gastrointestinal disorders (FGIDs) are common and distressing. They are so named because a defined pathophysiology in terms of structural or biochemical pathways is lacking. Traditionally FGIDs have been conceptualized as brain–gut disorders, with subgroups of patients demonstrating visceral hypersensitivity and motility abnormalities as well as psychological distress. However, it is becoming apparent that there are certain structural or biochemical gut alterations among subsets with the common FGIDs, most notably functional dyspepsia (FD) and irritable bowel syndrome (IBS). For example, a sodium channel mutation has been identified in IBS that may account for 2 % of cases, and subtle intestinal inflammation has been observed in both IBS and FD. Other research has implicated early life events and stress, autoimmune disorders and atopy and infections, the gut microbiome and disordered mucosal immune activation in patients with IBS or FD. Understanding the origin of symptoms in FGIDs will allow therapy to be targeted at the pathophysiological changes, not at merely alleviating symptoms, and holds hope for eventual cure in some cases. For example, there are promising developments in manipulating the microbiome through diet, prebiotics and antibiotics in IBS, and testing and treating patients for Helicobacter pylori infection remains a mainstay of therapy in patients with dyspepsia and this infection. Locally acting drugs such as linaclotide have been an advance in treating the symptoms of constipation-predominant IBS, but do not alter the natural history of the disease. A role for a holistic approach to patients with FGIDs is warranted, as brain-to-gut and gut-to-brain pathways appear to be activated.     

Functional dyspepsia and duodenal eosinophilia: A new model

Functional dyspepsia (FD) is a highly prevalent disorder that affects more than 10% of the population. In the past decade, the theoretical underpinning of the concept of FD has begun to change, in light of new data on the underlying pathophysiological mechanisms of this disorder, with a focus on the duodenum. The Rome IV criteria, published in 2016, note that gastroesophageal reflux disease and irritable bowel syndrome overlap with FD more than expected by chance, suggesting that they may be part of the same disease spectrum. Infection by Helicobacter pylori (H. pylori) may explain a minority of cases of FD and in the Rome IV criteria H. pylori‐associated dyspepsia (defined as symptom relief after eradication therapy) is considered a separate entity. Duodenal inflammation characterized by increased eosinophils and in some cases mast cells, may impair the intestinal barrier. Post‐infectious gastroenteritis is now an established risk factor for FD. Other risk factors may include atopy, owning herbivore pets and exposure to antibiotics, together with gastroduodenal microbiome disturbances. Small bowel homing T cells and increased cytokines in the circulation occur in FD, correlating with slow gastric emptying, and a possible association with autoimmune rheumatological disease supports background immune system activation. A genetic predisposition is possible. FD has been linked to psychological disorders, but in some cases psychological distress may be driven by gut mechanisms. Therapeutic options are limited and, aside from responders to H. pylori eradication, provide only modest and temporary relief. Advances in understanding FD may alter clinical practice, and the treatment of duodenal inflammation or microbiome alterations may lead to a cure for a subset of these patients in the future.     

Complete regression of primary gastric plasmacytoma following<Emphasis Type="Italic"> Helicobacter pylori</Emphasis> eradication

We describe the first case of a primary gastric plasmacytoma stage I completely regressed following Helicobacter pylori (H.pylori) eradication. The patient, a 61-year-old man, had a long history of chronic gastritis and gastric ulcers with recurrent gastrointestinal hemorrhage. Diagnosis of H.pylori infection was based on the positive urease breath test, the elevated titers of serum anti-H.pylori antibodies, and the detection of the bacterium in gastric mucosa biopsy specimens. Diagnosis of gastric plasmacytoma was based on the findings of histopathology, immunocytochemistry and in situ hybridization. Eradication of H.pylori with antibiotics was followed by disappearance of endoscopic and histopathologic features of the gastric tumor 3 months after the completion of the treatment. No relapse has been documented 20 months after the initial diagnosis of plasmacytoma. A possible causal relationship between the tumor and the underlying H.pylori infection is discussed.     

Zollinger-Ellison syndrome

SinceHelicobacter pylori infects the gastric mucosa in most patients with chronic duodenal ulcer, infection with this organism has been implicated in the pathogenesis of this common disease. We postulated that ifH. pylori is pathogenic in the usual type of duodenal ulcer, it should be less common when duodenal ulcer has another, specific etiology, such as Zollinger-Ellison syndrome. Gastric mucosa was compared from 18 patients with proven Zollinger-Ellison syndrome (17 of whom had had duodenal ulcer disease) and 18 controls with chronic duodenal ulcer without such a diagnosis. All subjects, who were matched for age and sex, had undergone elective gastric resections. Gastric tissues were stained by hematoxylin-eosin and Giemsa and were reviewed by an experienced pathologist who was unaware of the diagnosis. The frequency ofH. pylori in patients with Zollinger-Ellison syndrome (8/18) was lower than in controls with duodenal ulcer (16/18;P<0.02). Moreover, chronic antral gastritis scores were higher in patients with duodenal ulcer (P<0.01). In Zollinger-Ellison syndrome, peak acid output was lower in patients positive (median 22 meq/30 min) compared to those negative forH. pylori (median 32 meq/30 min;P<0.02) but serum gastrin was correspondingly lower in patients positive forH. pylori (P<0.05).H. pylori infection appears to be more frequent when duodenal ulceration is not associated with another etiology, such as acid hypersecretion in Zollinger-Ellison syndrome.H. pylori infection in Zollinger-Ellison syndrome may also be associated with decreased gastric acid secretion.Supported in part by grant DK34988 from the National Institutes of Health, U.S. Public Health Service.This work was presented in part at the American College of Gastroenterology Annual Meeting, New Orleans, October 1989, and published in abstract form in theAmerican Journal of Gastroenterology (84:1159, 1989).     

Treatment of Helicobacter pylori infection:Current status and future concepts

Helicobacter pylori(H.pylori)infection is highly associated with the occurrence of gastrointestinal diseases,including gastric inflammation,peptic ulcer,gastric cancer,and gastric mucosa-associated lymphoid-tissue lymphoma.Although alternative therapies,including phytomedicines and probiotics,have been used to improve eradication,current treatment still relies on a combination of antimicrobial agents,such as amoxicillin,clarithromycin,metronidazole,and levofloxacin,and antisecretory agents,such as proton pump inhibitors(PPIs).A standard triple therapy consisting of a PPI and two antibiotics(clarithromycin and amoxicillin/metronidazole)is widely used as the first-line regimen for treatment of infection,but the increased resistance of H.pylori to clarithromycin and metronidazole has significantly reduced the eradication rate using this therapy and bismuth-containing therapy or 10-d sequential therapy has therefore been proposed to replace standard triple therapy.Alternatively,levofloxacin-based triple therapy can be used as rescue therapy for H.pylori infection after failure of first-line therapy.The increase in resistance to antibiotics,including levofloxacin,may limit the applicability of such regimens.However,since resistance of H.pylori to amoxicillin is generally low,an optimized high dose dual therapy consisting of a PPI and amoxicillin can be an effective first-line or rescue therapy.In addition,the concomitant use of alternative medicine has the potential to provide additive or synergistic effects against H.pylori infection,though its efficacy needs to be verified in clinical studies.     

New Approaches to Diagnosis and Treatment of Functional Dyspepsia

Purpose of Review

The purpose of this article is to review the recent literature and discuss the new approaches to the diagnosis and treatment of functional dyspepsia (FD).

Recent Findings

According to the recent American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) guideline for dyspepsia, Helicobacter pylori (H. pylori) eradication is recommended as a first treatment option, and proton pump inhibitors (PPIs), tricyclic antidepressants, and prokinetics are listed as second-line therapy. On the other hand, in the Japanese guideline for FD, PPIs and prokinetics are recommended as the first-line treatment. In Japan, acotiamide, a recently launched prokinetic, showed significant efficacy in several clinical trials performed either in Japan or Europe. Regarding non-pharmacological treatment, recent topics include acupuncture, electrical stimulation, gastric peroral endoscopic myotomy, and meal and lifestyle modification. These treatments have provided significant efficacy, which provides some insights into the main pathophysiology of this disease.

Summary

Although FD is common among functional gastrointestinal disorders, it is not easy to relieve the dyspeptic symptoms of FD patients. Combinations of pharmacological and non-pharmacological treatment options are expected.

     

Relation among plasma ghrelin level, gastric emptying, and psychologic condition in patients with functional dyspepsia

BACKGROUND AND GOALS: Neurohormonal factors might play a role in the pathogenesis of functional dyspepsia (FD). However, the role of ghrelin, a gastrointestinal hormone that stimulates gastric motility, in FD is not yet clearly defined. The present study was designed to investigate plasma ghrelin levels and their relation with gastric emptying and psychologic status in FD. METHODS: Sixteen patients with FD of the dysmotility type and 19 healthy controls were enrolled in the study. Plasma active and desacyl ghrelin concentrations before and after test meal were measured by enzyme-linked immunosorbent assay. Gastric emptying and psychologic condition were studied using C acetate breath test and questionnaires, respectively. RESULTS: Gastric emptying was significantly prolonged in patients with FD compared with controls. Fasting desacyl and total ghrelin levels were significantly lower in FD patients than in controls, but fasting active ghrelin levels and postprandial levels of ghrelin in both forms were similar between the 2 groups. Fasting total ghrelin levels in FD patients did not differ from the postprandial levels, in contrast to what was found for controls. There was no significant association among gastric emptying, plasma ghrelin levels, and psychologic factors in FD patients. CONCLUSIONS: Total secretory ability or metabolic condition of ghrelin may be altered in patients with FD. This seems to play a role in the pathophysiology of dysmotility type FD, independent of delayed gastric emptying or psychologic disorders.