Fass R., Tougas G. Functional heartburn: the stimulus, the pain, and the brain. Gut 2002;51:885–892.
Functional heartburn: the stimulus, the pain, and the brain
R Fass, G Tougas
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Несмотря на значительный прогресс в наших знаниях о механизмах, коррелированных с гастроэзофагеальнм рефлюксом, наше понимание факторов, ответственных за симптомы, связанных с гастроэзофагеальной рефлюксной болезнью (ГЭРБ), остается ограниченным. Пациенты с неэрозивной рефлюксной болезнью (НЭРБ) составляют до 70% всех пациентов с ГЭРБ и служат ярким примером нашего незнания механизмов, лежащих в основе возникновения симптомов ГЭРБ. Важно признать разнообразие пациентов, сгруппированных в настоящее время под «зонтиком» НЭРБ, чтобы понять ее патогенез. Функциональная изжога является важной подгруппой НЭРБ, которая включает пациентов с воздействием кислоты в пищевод в физиологических пределах в дополнение к нормальным данным эндоскопии. Механизмы, ответственные за боль, клинические характеристики и оптимальный терапевтический подход остаются плохо изученными. Тем не менее, недавние исследования показывают, что функциональная изжога возникает у 50% пациентов с НЭРБ и является важным фактором непредсказуемого ответа на антирефлюксную терапию, наблюдаемого у пациентов с НЭРБ. Из-за размера этой подгруппы пациентов и сложности основных механизмов их симптомов требуются дальнейшие исследования для разработки эффективных терапевтических методов, которые, вероятно, не будут ограничиваться подавлением кислотности.
Functional heartburn is a common disorder and appears to be composed of several distinct subgroups. Identifying the different subgroups based on clinical history only is not achievable at present. The mechanisms responsible for pain, clinical characteristics, and the optimal therapeutic approach remain poorly understood. Response to potent antireflux treatment is relatively limited. Current and future treatment strategies for functional heartburn patients who have failed standard dose proton pump inhibitors (PPIs) include increased PPI dose in some, as well as addition of pain modulators in others.
Despite significant advances in our knowledge of the mechanisms leading to gastro-oesophageal reflux, our understanding of the factors responsible for the symptoms associated with gastrooesophageal reflux disease (GORD) remains limited. Subjects with non-erosive reflux disease (NERD) account for up to 70% of GORD patients in the community and serve as a striking example of our ignorance of the mechanisms underlying symptom generation in GORD. It is essential to recognise the diversity of patients presently grouped under the “umbrella” of NERD in order to understand its pathogenesis. Functional hearburn is an important subgroup of NERD that includes patients with oesophageal acid exposure within the physiological range in addition to normal endoscopy. The mechanisms responsible for pain, clinical characteristics, and the optimal therapeutic approach remain poorly understood. However, recent studies suggest that functional heartburn accounts for up to 50% of NERD patients and is an important contributor to the unpredictable response to antireflux therapy that has been observed in NERD patients. Due to the size of this patient subgroup and the complexity of the underlying mechanisms of their symptoms, further studies will be necessary in order to develop effective therapeutic modalities, which will probably not be limited to acid suppression.
Symptoms are the primary reason for patients to seek medical attention. Most clinic visits are due to symptoms and physicians spend much of their professional life dealing with symptoms.1 In the last century medical research has focused mainly on disease processes rather than symptoms.2 This focus has transformed medicine from a descriptive field to one that explains mechanisms of disease.1 In fact, in the last century students in medical schools have been introduced to the prevailing motto that successful treatment of diseases is achievable only by addressing the underlying mechanism. However, this change in attitude towards diseases came at a high cost: our understanding of symptoms of many medical disorders remains extremely poor. Furthermore, we have raised generations of physicians that are sceptical of symptoms when objective confirmation cannot be found.1,3,4
The emphasis on disease processes rather than symptoms has not spared the study of GORD. Despite significant progress in our understanding of the mechanisms that lead to gastrooesophageal reflux, we have made very little progress in understanding symptoms. Recognition of transient lower oesophageal sphincter relaxation (TLOSR) as the main cause for physiological and pathological acid reflux is a typical example.5,6 While responsible for most acid reflux events, in reality TLOSRs are rarely associated with symptoms as most acid reflux events that occur in GORD patients or in healthy subjects are never perceived7 (fig 1).
Remarkably, the exact causes responsible for GORD symptoms continue to elude us. Part of the problem is our obsessive focus on the oesophageal mucosal injury produced by excessive acid reflux rather than on symptoms per se. For decades, almost all the therapeutic trials in GORD have concentrated almost exclusively on oesophageal healing rates and on symptomatic responses in patients with erosive oesophagitis only. Very few therapeutic trials have been conducted in patients with NERD, and even less on symptom generation in this subset of patients.
Another aspect of the problem is the lack of association between symptom severity or frequency and the presence or absence of oesophageal inflammation.8 Furthermore, there is no association between symptom severity and the extent of oesophageal mucosal injury. Using data pooled from 16 independently conducted clinical treatment trials, Carlsson et al examined the prevalence of heartburn symptoms in patients with or without erosive oesophagitis.9 Their meta-analysis convincingly showed that moderate to severe heartburn was as prevalent among patients with grade 1 (mucosal erythema) or grade 2 (non-circumferential erosions), with a respective prevalence of 71.7% and 75.8%, as patients with grade 3 (circumferential erosions) and grade 4 (oesophageal ulceration) where the prevalence of heartburn was 74.4% and 64.2%, respectively.9 Other symptoms, such as acid regurgitation, were also equally prevalent among patients with little or no mucosal injury and those with erosive oesophagitis.
In recent years, more attention has been directed towards patients with NERD. This stems from several pivotal therapeutic GORD trials that were conducted in patients recruited in the community rather than tertiary practices. Two important findings emerged from these studies: firstly, most community patients with heartburn have no oesophageal mucosal injury. Secondly, and this is a priori somewhat surprising, patients with typical GORD symptoms but a normal oesophageal mucosa demonstrate lower rates of symptom improvement with potent antireflux treatment than patients with erosive oesophagitis.10 These findings require us to reassess our understanding of the mechanisms that lead to symptom generation in GORD, particularly in patients with normal oesophageal mucosa.
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