Elektrogastrografie u systémové sklerodermie – pilotní studie

Souhrn

Úvod: Systémová sklerodermie (SSc – systemic sclerosis) je autoimunitní onemocnění s chronickým progresivním průběhem. Patogeneze SSc je charakterizována zánětem, vaskulopatií a fibrózou. Mezi nejčastěji postižené orgány patří gastrointestinální trakt, a to až u 90 % nemocných. Klinické projevy jsou spojeny s dysmotilitou všech částí gastrointestinálního traktu, vč. žaludku. Elektrogastrografie (EGG) je neinvazivní metoda pro vyšetření žaludeční myoeletrické aktivity.

Cíl: Cílem této prospektivní studie bylo podrobně posoudit EGG u SSc, vč. analýzy jednominutových intervalů a plochy amplitud.

Metoda: Do studie bylo zařazeno 33 pacientů splňujících klasifikační kritéria SSc podle ACR/EULAR (5 mužů, 28 žen; průměrný věk 60 let). Pacienti byli rozděleni na klinické podskupiny: difúzní kožní forma SSc (dSSc) (n = 17), limitovaná kožní forma (lSSc) (n = 13) a ostatní (n = 3). Žaludeční myoelektrická aktivita byla vyšetřována pomocí EGG (MMS, Enschede, Nizozemsko)

Výsledky: Celkem bylo vyhodnoceno 855 jednominutových intervalů EGG, u každého z nich byla hodnocena dominantní frekvence a posouzena plocha amplitud. Pouze jeden pacient měl plně normální EGG záznam. U většiny pacientů se EGG vyznačovala bradygastrií (17 pacientů) nebo žaludeční arytmií s převahou bradygastrie (6 pacientů). Postprandiální plocha amplitud se výrazně snížila ve srovnání s hodnotami nalačno. Poměr ploch amplitud po jídle: před jídlem byl ve všech intervalech nízký. Závěr: Bradygastrie a postprandiální snížení plochy amplitud byly nejcharakterističtějšími nálezy. Tyto změny byly obzvlášť vyjádřené u skupiny dSSc.

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Dedikace: Tato práce byla podpořena projektem SVV 260542/ 2020 z Univerzity Karlovy a výzkumným projektem Progres Q40-15 z Univerzity Karlovy.

Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bio medicínských časopisů.

Klíčová slova:

systémová sklerodermie – elektrogastrografie – žaludeční myoelektrická aktivita – dominantní frekvence – elektrogastrografická síla

Introduction

Systemic sclerosis (SSc) is a connective tissue disease with a chronic and progressive course. Inflammation, vasculopathy and fibrosis play an important role in the pathogenesis of SSc [1]. The gastrointestinal tract is one of the most commonly involved organ systems in SSc and is present in up to 90% of patients with SSc. Any part of the gastrointestinal tract can be affected [2]. Most commonly, the involvement of oesophagus and stomach is observed; yet, an impairment of the small bowel function with the syndrome of intestinal bacterial overgrowth can complicate the condition [3,4].

The pathological processes contributing to the gastrointestinal involvement in SSc are complex and are leading todifferent gastrointestinal motor disorders. Neuropathy, followed by myopathy and later on by fibrosis production, is a crucial moment in the pathophysiology of the disease. The presence of specific antibodies support the above: autoantibodies against acetylcholine M3 receptor (anti-M3R) causing significant smooth muscle dysfunction in early phase of gastrointestinal involvement in SSc have been detected [2].

The stomach in SSc can be affected by various motility dysfunctions, including impaired interdigestive and postprandial gastric motor pattern, delayed gastric emptying and/or can be associated with chronic atrophic gastritis [5].

The surface electrogastrography (EGG) is a non-invasive method for assessment of gastric myoelectrical activity. A gastric pacemaker generates an electrical phenomenon termed “gastric slow waves”. They originate in a “pacemaker region” located on the greater curvature of the stomach near the junction of the fundus and proximal gastric body [6]. A method of examining a signal by frequency instead of time has been implemented mathematically and is called the Fourier transform. The dominant frequency is determined as a frequency with the greatest power in the Fourier transform during a specific time period. The power is defined as an area of waves (amplitudes) [6]. The normal gastric slow-wave frequency corresponds to 3 cycles per minute (a 3-cmp rhythm) [6–9]. The values of 0.5–2.0 cpm are referred to bradygastria, the values of 4–9 cpm are called tachygastria, and the last gastric dysrhythmia is an arrhythmia in which non-rhythmic gastric slow waves occur [9]. EGG is feasible both for experimental studies [10–16] and clinical assessment [6,7,17–24]. Only a few papers investigated EGG in SSc so far [25–33]. Bradygastria was the most important finding in those studies. To the best of our knowledge, no in-depth EGG analysis in SSc has been published so far. The aim of our prospective study was to investigate EGG of SSc in detail, including the analysis of one-minute intervals and evaluation of EGG power.

Materials and methods

Patients

The study group included 33 patients (5 men, 28 women, mean age 60 years, min. 22, max. 83 years). All patients met the criteria for SSc determination according to the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) from 2013 [34]. The limited SSc (lSSc) and diffuse SSc (dSSc) subsets were based on differences in the extent of skin involvement [35]. Totally 17 patients (including 2 men) suffered from dSSc and 13 patients (including 2 men) had lSSc. Sclerosis sine scleroderma was seen in two subjects, one male patient suffered from an overlap syndrome. The mean age of patients at the time of the diagnosis was 51 years (10–80 years). The average time from the onset of the first symptoms to the diagnosis was 5 years (the shortest period to the diagnosis was 1 month, the longest 34 years). The most common initial non-Raynaud’s symptom was the joint pain (11 patients; including 1 male) and skin stiffness (11 patients; including 1 male). Other symptoms were: dyspnoea (5 patients; including 1 male), heartburn (4 patients), digital ulcers (4 patients), joint swelling (3 patients; including 1 male), cough (3 patients), muscle weakness (3 patients), dysphagia (2 patients), oedemas of lower extremities (1 male patient), palpitations (1 patient), diarrhoea (1 patient), chest pain (1 patient), Sjögren’s syndrome (1 patient) and arterial hypertension (1 male patient). Totally 18 patients had more than one symptom. Five patients kept smoking, twelve stopped smoking and 16 individuals have never smoked.

Electrogastrography

Our original method of EGG has already been published elsewhere [14]. Briefly, six active self-adhesive electrodes were placed on the upper part of the abdomen; the 7^th electrode (basal one) was placed in the left supraclavicular area. A special abdominal belt (respiratory sensor) was used to identify possible artefacts due to breathing and body movements (Fig. 1). The gastric myoelectric activity was investigated using an EGG stand (MMS, Enschede, the Netherlands). All EGGs were accomplished at a supine position in the morning after overnight fasting. The first 15-minute interval was recorded in patients who have been fasting and have been awake during the whole period of recording. Fifteen minutes after a standardized breakfast had been completed, the following 15 one-minute postprandial intervals were recorded. All files were archived for further assessment. EGG was evaluated by MMS software (version 8.19). Running spectral analysis was used for a standard evaluation of EGG. The results were expressed as a dominant frequency of the gastric slow waves and the power analysis and power ratio assessment as a fraction of the areas of the amplitudes after (numerator) and before (denumenator) the standardized breakfast.

Statistical analysis

The data were statistically treated by means of descriptive statistics, non-paired t-test, Mann-Whitney rank sum test and Pearson product-moment correlation using the SigmaStat software (Version 3.1, Jandel Corp, Erkrath, Germany).

Ethics

The study was approved by the Joint University Ethics Committee (Protocol number DSP_GIT_SSc, ref. no. 201805 S07P). All procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its latter amendments.

All patients signed a written consent. For all data obtained, all personal identification information was deleted in compliance with the laws for the protection of confidentiality of the Czech Republic.

Results

High-quality recordings were obtained and these enabled unequivocal final conclusions in all subjects. Altogether 855 one-minute EGG intervals were evaluated, each in dominant frequency, power and power ratio (Tab. 1, Fig. 2 and 3, Graphs 1–3). Only one patient (3%) had a completely normal EGG (Fig. 4). Most patients had bradygastria (17 patients, including 4 men) (Fig. 5) of which 59% suffered from dSSc and 24% lSSc; 12% had sclerosis sine scleroderma and 6% an overlap syndrome. Another 6 patients (including 1 man) had gastric arrhythmia with a predominance of bradygastria (Fig. 6), 6 patients had gastric arrhythmia and 2 patients had a non-specific abnormal EGG, with no differences between dSSc and lSSc. One patient with lSSc had a combination of gastric arrhythmia, bradygastria and tachygastria. There was a significant increase in postprandial dominant frequency compared to basal recording, with a peak at 8 minutes of postprandial EGG (P = 0.020) (Graph 1). The postprandial power decreased significantly, with a minimum observed at the 3^rd minute (P = 0.009) (Graph 2). The power ratio was low in all intervals.

Discussion

Our current study has shown novel important data on gastric myoelectric activity in SSc. This is the first study providing a detailed analysis of EGG recordings in SSc. We evaluated particular one-minute intervals during the fasting period and after a test meal. Pathological or abnormal EGGs were found in all patients with the exception of one individual. Bradygastria was the most common finding, which is in a good agreement with other studies published so far [25–29,32]. Yet, our most important finding was the low postprandial EGG power. In a healthy adult subject, twofold increase in EGG power should be observed after a test meal [6–8]. In SSc, we found a significant decrease in the postprandial power compared to the recordings during the fasting period. The power ratio was low in all the evaluated time intervals. This is an important proof of both structural involvement and functional disorder of the stomach in SSc.

On the other hand, EGG was completely normal in one patient only. This was a 70-year old woman with a lSSc diagnosed 3 months before EGG was accomplished. There were no gastrointestinal symptoms at the initial clinical manifestation of SSc. According to the theory, which is taking into account the anti-M3R antibodies, neuropathy is observed in the early phase of the gastrointestinal involvement. This is followed by a myopathic (atrophy of smooth muscle) phase and a fibrotic phase. This would be in agreement with our study, where bradygastria was less frequent in lSSc forms of the disease. Moreover, patients usually do not develop a multiple organ involvement simultaneously in the very early stages of SSc (Graphs 2,3).

Bradygastria is also typically observed in anorexia nervosa [36,37], in diseases associated with neuropathy, in connective tissue diseases group [38–40] and in the early phases after an abdominal surgery [18,19,22–24]. This is a broader basis for the study of the etiopathogenesis of gastric dysrhythmias including bradygastria.

In the literature, authors have focused on plasma levels of various substances that could affect dysrhythmias. For example, the gastrointestinal peptides motilin, ghrelin, vasoactive intestinal peptide or interleukin-6 (IL-6), antibodies against muscarinic acetylcholine receptors (AChRs) and myenteric neurons and specific antibodies which inhibit acetylcholine receptor anti-M3R have been studied in this context [2,22,23,32,33,36–45].

In SSc, plasma concentrations of motilin have shown positive correlation with dysrhythmia and negative correlation with normal slow wave rhythm [32]. Ghrelin was studied in anorexia nervosa, where bradygastria also occurs [36,37]. Insufficient release of gastrointestinal peptides, especially ghrelin, has been confirmed in anorexia nervosa [41,42].

Specific antibodies against muscarinic AChRs and myenteric neurons have also been found to have an association with gastrointestinal dysmotility; not only in SSc but also in rheumatoid arthritis and other systemic diseases [38–40]. Specific antibodies against M3R cause a significant smooth muscle dysfunction in SSc patients by inhibiting acetylcholine binding to anti-M3R [2,43–45]. The neutralization of anti-M3R antibodies by human intravenous immunoglobulins and its antigen-binding fragment F (ab) 2 might reverse the intestinal dysfunction and are being considered as a potential targeted therapy [2,46].

Surgical studies in which bradygastria correlated with IL-6 serum concentrations demonstrate that IL-6 also affects the gastric motility. It has been shown that IL-6 can promote early systemic inflammatory response to gastric myoelectric activity [22,23]. Studies have documented that bradygastria disappeared after a certain period (1 to 2 days) after the operation [18,19,23,24] and concentrations of IL-6 decreased [23]. Similar results were also demonstrated by others [32,33]. Interestingly, anti-IL-6 treatment improved autonomic dysfunction in patients with rheumatoid arthritis [47].

Current options for the diagnosis of motor dysfunction of the stomach are gastric scintigraphy, 13C-octanoic acid breath tests, wireless motility capsule, antroduodenal manometry, ultrasonography and magnetic resonance imaging [48–54]. EGG is a non-invasive, reliable, potentially useful method in the diagnosis of gastric motility disorders in SSc.

We are aware of possible limits of this pilot study. We have not enrolled a group of healthy individuals. We relied on our previous healthy controls [8] and on the data from literature [6,7]. Nevertheless, our findings were very consistent in the majority of our patients. We did not correlate EGGs with either subjective dyspeptic symptoms or other possible variables. We plan to repeat a detailed investigation of the gastric myoelectric activity in SSc during a follow-up of the patients in the near future.

Conclusion

A pathological EGG was a constant finding in our set of patients suffering from SSc. Bradygastria and postprandial decrease of the power were the most characteristic features. These findings were confirmed especially in the dSSc subgroup. Further studies are needed to characterize clinical significance of these features precisely.

Acknowledgment

The authors are much obliged to Bc. Dita Staníčková and Mgr. Veronika Balášková for their brilliant skill and excellent technical cooperation.

Conflict of Interest:

The authors declare that the article/ manuscript complies with ethical standards, patient anonymity has been respected, and they state that they have no
fi nancial, advisory or other commercial interests in relation to the subject matter.

Publication Ethics: This article/ manuscript has not been published or is currently being submitted for another review. The authors agree to publish their name and e-mail in
the published article/ manuscript.

Dedication: This work was supported by the project SVV 260542/ 2020 from Charles University and by the research project Progres Q40-15 from Charles University.
The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for bio medical papers.