TO THE EDITOR
Gastroparesis, characterized by a gastric emptying (GE) delay in the absence of mechanical obstructions, represents one of the most difficult diabetic complications to treat, which in turn may lead to very serious and at times life-threatening complications[1]. Despite being often overlooked, it has a high prevalence in type 1 diabetics (40%) and lower in type 2 diabetics (10%-20%)[2] with a rising trend of incidence correlated with that of diabetes[3]. It is clinically characterized by typical postprandial symptoms, such as nausea, vomiting, bloating, early satiety, epigastric pain and is causally associated with damage to the enteric nervous system (ENS) with neuromuscular inflammation[4].
Remarks on gastric neuropathy pathophysiology
Chronic hyperglycemia is the main factor responsible for the progressive damage, not only of the gastric enteric neurons, including nitrergic, serotonergic and dopaminergic ones, impairing their function up to cell death, but also of glial cells supporting enteric neurons[5], and, above all, the interstitial cells of Cayal (ICC), coordinating antral peristalsis[2,6]. The damage is causally associated with a complex interaction of multiple factors, such as increased levels of oxidative stress, loss of expression of neuronal nitric oxide, mitochondrial dysfunction, immune and inflammatory responses, microvascular complications with ischemia, alterations of neurotrophic factors and neurotransmitters, etc.[2]. Furthermore, it is necessary to hold in due consideration a new entry in diabetic gastroparesis (DG) pathophysiology, the relationship between gut microbiota and diabetic enteropathy. This relationship is bilateral, in the sense that gastric stasis due to enteropathy can modify gut microbiota up to dysbiosis, whereas the latter produces from the nutrient, a multitude of noxious, innocuous or beneficial metabolites, among which there are many neurotransmitter-like molecules, such as gamma-aminobutyrric acid, serotonin, melatonin, histamine, and acetylcholine, able to act on ENS and influence gut motility and transit[6] and other substances able to induce the generation of trophic factors, including glia-derived neurotrophic factor, through activation of toll-like receptors[7].
The neural alterations are progressive and cause an impairment of gastric motor a activity with a continuous worsening of the GE delay, leading to gastroparesis[2].
Complications of gastroparesis
This disease is a complication that in turn causes further complications. First of all, it interferes with glycemic therapeutic control. In fact, the more or less delayed GE makes it difficult to establish the right timing for the administration of insulin and oral antidiabetics in relation to meals. If we give insulin before a meal to a diabetic patient with gastroparesis at the same time-interval as that used for a diabetic patient with a normal GE, we risk causing hypoglycemia, because, when insulin comes into action, the food is still in the stomach. Conversely, if the food arrives in the intestine when the action of insulin has worn off, this risks causing hyperglycemia. Unfortunately, both hypoglycemia and hyperglycemia cause further damage to the enteric neurons. As regards oral antidiabetics, the problem is complicated by the fact that the tablets, once ingested, may remain in the stomach for a longer time than in a diabetic patient without delayed GE before reaching the intestine, where they are absorbed, going on to carry out their action with unpredictable effects.
Another serious complication of gastroparesis consists of the progressive worsening in the nutrition status, because the unpleasant gastric symptoms lead to poor food intake and, at times, scarce liquid ingestion, causing a deficit in calories, vitamins and minerals as well as a state of dehydration, chiefly in the presence of vomiting[8].
A further complication is the appearance of gastro-esophageal reflux (GER)[9], usually, but not always, announced by the appearance of burning or painful epigastric sensations and/or acid regurgitation. This complication raises fears of another more serious one, that is the aspiration of gastric material into the airways. GER is favored by gastric stasis, which in some cases could be facilitated by the use of a hypoglycemic agent, the glucagon-like peptide 1 receptor agonist (GLP-1RA). In fact, this drug, beside stimulating insulin secretion in type 2 diabetics, slows down GE[10] and induces gastric stasis[11]. On the one hand this fact, is positive, as it reduces postprandial glycemia, but on the other it becomes negative in case of gastroparesis, increasing gastric stasis, which favors acid regurgitation. This condition is feared by anesthetists[12-14], because the copious gastric content, demonstrated by means of preoperative endoscopy[15], could regurgitate into the airways during the induction of general anesthesia, even when the patient has respected the pre-operative fast. I have found only two case reports under treatment with a GLP-1RA in PubMed[16,17], who, despite the preoperative fasting guidelines, had pulmonary aspiration. In one of them[16] with Barrett's esophagus due to GER, it was necessary to suction out the abundant gastric content and remove food remains from the trachea and bronchi using bronchoscopy. However, a review concerning articles regarding the aspiration/regurgitant events related to GLP-1 RAs in a variety of patients carried out by Chang et al[18] stated that the currently available data do not suggest a significant increase in aspiration and regurgitation events associated with the use of GLP-1RAs, but concluded that “large randomized controlled trials may be helpful to further elucidate the impact of GLP-1 RAs on perioperative aspiration risk”. However, in patients with DG, to minimize the risk of regurgitation events and pulmonary aspiration many major societal guidelines currently recommend withholding GLP-1RAs prior to surgery, a measure deemed insufficient by some investigators[19]. Others, in addition, raise the concern that prolonged cessation of GLP-1 RAs treatment could have a detrimental effect on peri-operative glycemic control[20]. As a long-standing motilist, I would suggest, instead of stopping this drug, another simple procedure, partly derived from the article of Jalleh et al[19]. After a blended food diet during the week before surgery, gastric ultrasound should be performed just before anesthesia[21] to look for gastric content, to be aspirated with a nasogastric tube, if abundant. Obviously, this proposal needs to be confirmed by controlled trials before implementation.
When, how and for whom should early diagnosis of gastroparesis be made?
As seen above, there are many reasons why DG should be diagnosed as early as possible, but, above all, because in this way there is more time available for a therapeutic intervention to slow down the progression of enteric neuropathy, before the gastric neurons with the glial cells and the ICCs, which control gastric peristalsis, have gone completely haywire.
But how can this goal be achieved? And what diabetic patients running this risk should be taken into consideration for appropriate measures?
Following Camilleri et al[2] a suspicion of this disease should arise especially in patients with type 1 diabetes at any time (40%) and in patients with long standing type 2 diabetes (10%-20%) when the physician encounters difficulties in establishing an appropriate and stable glycemic level and when the patient reports to the physician some of the gastric symptoms typical of the disease, albeit slight. Unfortunately, the perception of visceral disorders varies considerably from one individual to another and the typical symptoms, such as nausea, vomiting, bloating, and early satiety often appear when the disease is in full swing. In fact, many patients with delayed GE are asymptomatic; whereas others have mild-to-moderate symptoms of indigestion[4] and hardly see their doctor. When these at risk patients consult their doctor, also for other problems, the latter ought to inquire as to whether they have dyspeptic symptoms and must not underestimate them even when reported spontaneously by the patients. In addition, it is also necessary to check for other contingent and concomitant causes that may slow down GE, such as drugs, etc. before the test.
How to find a GE delay
Obviously, one cannot rely on symptoms alone to make an early diagnosis of gastroparesis. Hence, it is necessary to look for the main objective sign of altered antral motility, that is delayed GE, the mark of gastroparesis.
There are various methods for assessing this parameter, such as the “gold standard” scintigraphy, that perfectly measures the GE of a radio-labeled meal, but exposes the patients to radiations, not always accepted by them, as well as breath tests, such as those with 13C octanoic acid or 13C spirulina algae[22], which, however, are an indirect test of GE and take a longtime to have the result. Furthermore, there is the method based on GE of ingested radiopaque markers detected by X-rays[23], which is not physiological, involves exposure to radiations and is only useful in patients with a full-blown disease, while the one performed with magnetic resonance imaging[24] is very good, but is costly and requires scarcely available equipment. In addition, there are also the latest innovative techniques, such as capsule endoscopy and smart pills, capable of measuring, besides endoluminal pressure, even pH, and temperature, offering a less invasive and reliable method to directly visualize gastro-intestinal functions[25], but they are non-physiological and, in addition, are too expensive for this type of investigation.
There is a simple, non-invasive, physiological, safe, reliable, and easily available method to measure GE: The real-time ultrasonography of the gastric antrum. The result is achieved after the ingestion of a meal through the measurement, at established times, of the cross-sectional area of the gastric antrum. This is, cranially, delimited by a vertical line passing across the angular incisure of the stomach and, distally, by the pyloric closure. This test can be performed with two different procedures, aimed one to obtain the final GE time and the other the rate of GE.
With the first procedure[26,27], only the final emptying time is calculated, starting from the ingestion of a standardized, bromatological equilibrated and semi-solid meal of 800-kcal, by measuring the antral area at regular 30-minute intervals until it returned to basal value. However, although this procedure gives accurate results, it takes a lot of time, because the empty stomach is reached after 248 +/- 39 min (mean +/- SD) in a series of 54 healthy subjects[26]. Consequently, it would take several hours in patients with markedly delayed GE and such a long period of time is hardly available in the clinical practice.
With the other procedure[28], the total time spent is much shorter, because only the GE rate was evaluated, which was expressed as antral area percent reduction from 15th to 90th min after the ingestion of a standardized, semi-solid breakfast meal of 330 kcal. This study was carried out in diabetic patients with dyspeptic symptoms, showing a GE rate median value of 29%, significantly lower than that of healthy subjects, which was 63%.
The first procedure is more suitable for research studies, while the second is by far preferable for diagnostic management of diabetic patients at risk of developing DG.
The ultrasonographic test has been proven to be a valid alternative to the scintigraphy test[29] and could be performed annually, at low cost, in diabetic patients at risk, as those with long-standing diabetes type 1, or with mild dyspeptic or autonomic symptoms or with difficulty in maintaining a stable glycemic level.
Quite recently, an interesting technique, namely ”body surface gastric mapping” (BSGM), able to detect gastric bio-electrical signals from the stomach through an array of electrodes placed on the skin’s thoraco-abdominal surface and to analyze the spatio-temporal patterns of gastric dysrhythmias, as an indicator of antral dysmotility and initial gastroparesis, has been proposed[30]. The idea is interesting, straightforward, non-invasive and safe, but does not take into account the fact that the delayed GE in gastroparesis may be due, not only to antral dysmotility detectable with BSGM, but also to impaired pyloric relaxation upon arrival of antral peristalsis (pylorospasm) and, sometimes, to duodenal dysmotility, which does not allow the transit of chimus arriving from the stomach[23]. Pylorospasm, which was observed in fourteen out of 24 diabetics, in a study by Mearin et al[31], forms part of the widespread disruption of enteric neuropathy that affects some diabetic patients. Unfortunately, as the BSGM technique only provides information on the condition of gastric motility and does not detect the presence of pylorospasm, it could find a normal antral motility, giving the impression that everything is all right, whereas GE is already delayed. In addition, BSGM faces several challenges that need to be overcome, such as anatomical variability, weak signal detection, noise and artifacts, reliance on complex algorithms, distinguishing gastric from colonic activity and issues with electrode placement and skin contact[30] and, therefore, requires an adequate control.
Once a reliable test for GE has been found, another problem arises
The GE value, obtained by any method, should reflect the GE capability, but it could be invalidated by the glycemic levels. In fact, some studies have found that hyperglycemia tends to delay GE[32,33], whereas hypoglycemia accelerates it[34]. Bharucha et al[4] found that up to 50% of patients with type 1 and type 2 diabetes and suboptimal glycemic control have delayed GE, measured with scintigraphy, 13C breath tests, or a wireless motility capsule, whereas the remainder of the patients have normal or accelerated GE.
Camilleri et al[2] reported that 50% of diabetics are at risk of gastroparesis, whereas its prevalence in type 1 diabetics, was 40 %, and in type 2 it was 10%-20 %. I believe that probably in some of these cases, the delayed GE was induced by uncontrolled hyperglycemia.
Another unexpected finding of the above mentioned study of Barucha et al[4] is the accelerated GE in some diabetics. This finding, however, was observed only for a liquid meal, especially in patients with type 2 diabetes at its onset, probably due to a vagal dysfunction with impaired gastric fundus accommodation[2,35]. For this reason, the methods which use only liquid meals are considered non physiological. Furthermore, Goyal et al[36] described, on the one hand, an acute hypoglycemia with a rapid GE, presumably due to disruption of the gastric braking hormonal system acting via the gastric inhibitory vagal motor circuit and, on the other hand, an acute hyperglycemia with delayed GE, probably due to the gastric inhibitory vagal motor circuit.
Therefore, to obtain a GE value as close as possible to the real motor capabilities of the gastric antrum, it is important to perform the GE test while avoiding the influence of episodes of marked hyperglycemia or hypoglycemia and choosing periods with glycemic levels under correct therapeutic control.
Further problems regarding the attribution of GE delay
Having stated the delay in GE with precision, it is necessary to establish whether it is caused by an antral failure, or by a pyloric-duodenal functional obstacle.
The above-mentioned technique BSGM, may be useful in the procedure for establishing the cause of delayed GE, as it is able to record, not only a normal gastric electrical activity, generated by ICCs in fasting[37] and postprandial conditions[38], in normal subjects, but also dysrhythmias, as evidence of an antral failure, especially in diabetic patients with gastroparesis[30], even if the recording capacity is sometimes precarious[39] and it is unable to notice a pyloro-duodenal functional hurdle.
If a gastric dysrhythmia is recorded, we may conclude with sufficient certainty that the delayed GE is due to gastroparesis. On the contrary, if normal gastric electrical activity is observed both in fasting and postprandial conditions, then the pylorus or the duodenum are probably responsible for the delayed GE. In this case the study of a pyloric pressure profile and of duodenal pressure waves by means of high-resolution antro-pyloric–duodenal manometry will confirm whether pylorospasm or a duodenal motor dysfunction is the cause of delayed GE. However, the pylorospasm may be detected with the endoluminal functional lumen imaging probe (EndoFLIP), as explained later.
However, it could be the case that the dysrhythmia recorded with BSGM is due to the fact that the continuous effort to overcome the obstacle represented by the pylorospasm in the long run has decompensated the motor activity of the gastric antrum. This situation could be compared to that of a heart, which becomes decompensated due to the continuous effort to pump against an obstacle represented by a stenotic aortic valve. Therefore, it would be more appropriated to perform high-resolution antro-pyloro-duodenal manometry or EndoFLIP, even when BSGM finds a dysrhythmia.
The final problem. Is enteric neuropathy really the cause of the diagnosed GE delay?
Having established with certainty the existence of a delayed GE in a diabetic patient, how can we be sure that this is due to an autonomic neuropathy? It could be a straightforward functional gastric disorder, like many observed in non-diabetic individuals, characterized by dyspeptic symptoms. Then we should look for other signs of an ENS disorder, such as esophageal, intestinal, or anorectal dysfunctions, or symptoms of a general autonomic disorder, which, unfortunately, is a rare eventuality. Autonomic testing may provide indirect indicators of enteric neuropathy by assessing the integrity of the ENS[40]. Unfortunately, the identification of specific biomarkers in blood or stool samples, including inflammatory markers and gut peptides, is still an area of ongoing research, promising non-invasive diagnostic options[41]. However, even if biomarkers of gastroparesis were already available, presumably they would not be measurable at the onset of the disease. As a matter of acts, only the concomitant signs and symptoms of autonomic neuropathy, when present, are a very good clue, but this is a rare event.
However, even in the absence of an objective proof of enteric neuropathy, a delayed GE in a patient with long standing diabetes, difficult glycemic control and even mild dyspeptic symptoms, self-declared or revealed during the doctor’s investigation, in the absence of contingent causes, could be considered due to initial neuropathic gastroparesis, also because, nowadays, the treatment does not differ much from the non-neuropathic one.
What should be done after early diagnosis?
The early diagnosis of gastroparesis allows us to start treatment of the causes of the GE delay with the aim of avoiding, or at any rate slowing down, the deterioration of the antral motor activity with the progressive damage of the enteric neurons, glial cells and ICC up to their death.
First of all, to avoid this evolution and prevent further progression of autonomic neuropathy, it is essential to avoid chronic hyperglycemia with a strict glycemic control[42,43], possibly by using devices with continuous glucose monitoring and insulin pumps[43,44].
In addition, to ease the grinding work of the stomach it is important to reduce solid foods to small particles sizes[45], either by chewing them well, remembering the Latin saying: “prima digestio fit in ore” (the first digestion takes place in the mouth), or, more quickly, by using a mechanical or manual grinder. It is also necessary to eat small meals with a low content of fat, that slows down GE, and fibers, that, in addition to slowing down GE, may cause bezoars.
Furthermore, it is important to stimulate gastric motility with prokinetic drugs, in order not only to alleviate the symptoms, but also, to prevent a worsening of delayed GE, avoiding a prolonged gastric stasis, which in the long run leads to dilation of the gastric antrum. This distension of the antral wall, may on the one hand hinder peristalsis from forming the antral chamber that expels the chyme in the duodenum and on the other, it strains and thins the gastric wall, probably increasing the ischemic conditions of intramural neurons. This evolution of chronic distension is just a hypothesis and could become the subject of future research, because in a recent experiment by Chan et al[46] the acute distension of the porcine stomach “in vivo” induced gastric electrical dysrhythmias, which persisted for some minutes, disrupting the gastric slow wave entrainment of peristalsis.
However, instead of starting right away with prokinetics, as is usually done, I believe that, especially in the case of early diagnosis, it would be more appropriate to investigate the possible presence of a functional obstacle to the gastro-duodenal transit represented by pylorospasm, since this is present in a subset of patients with DG[31]. For this purpose, the patient should undergo the high-resolution antro-pyloric-duodenal manometry[47], or, at least, the EndoFLIP (Endoscopic Functional Lumen Imaging Probe) device[48]. If there is pylorospasm, while awaiting the effectiveness of a futuristic medical treatment heralded by Camilleri and Atieh[49], which should reverse the pyloric dysfunction by means of pharmacological approaches like those with opioid receptors antagonists and the nitric oxide mimer Sildenafil, the endoscopic pyloric botulinum toxin infiltration or the pyloric balloon dilation (BD) could be tried, whose effectiveness and references are reported further on. Currently, this non-surgical endoscopic treatment is applied to patients with refractory and severe gastroparesis , but I believe that, being minimally invasive, it could be also performed, provided that a functional pyloric obstacle is clearly demonstrated, before a heavy treatment with strong prokinetic and antiemetic drugs bearing a lot of side effects. This therapeutic proposal should be, of course, validated with appropriate studies before it is implemented.
The medical treatment
The basic medical treatment of DG, especially in the case of diagnosis of full-blown disease, is represented by prokinetics and antiemetics with the contribution of neuromodulators. I have surveyed and synthetically reported the characteristics of these medical treatments by consulting the articles of Grover et al[22], Camilleri and Atieh[49] and Acosta and Camilleri[50].
Prokinetics are medications that stimulate coordinated gastrointestinal contractions, enhancing propulsion of intra-luminal contents and can be used with satisfactory results in GP patients to increase GE. However, most of them may have, along with this ability, adverse effects, more or less frequent and severe.
The first of all prokinetics is Methoclopramide, a D2 receptor antagonist with some 5-HT4 receptor agonism, which on the one hand shows good prokinetic and antiemetic effects, and on the other can produce central nervous system (CNS) disorders, up to the irreversible tardive dyskinesia, However, despite this, it is the only prokinetic approved for gastroparesis by Food and Drug Administration (FDA), albeit with a limit of 3 months of administration to avoid the worst complication.
Then we have Domperidone, a dopamine D2 receptor antagonist, provided with satisfactory prokinetic and antiemetic activities, which is devoid of the above-mentioned CNS risks, because it does not cross the blood-brain barrier, but is burdened by the risk of serious cardiac arrhythmias related to the prolongation of QT interval of ECG, up to sudden death, and therefore is only available for prescription through the FDA's program for Expanded Access to Investigational Drugs.
Cisapride, a 5HT4 agonist, is another effective prokinetic and antiemetic drug, but has been abandoned in most countries for drug-induced long QT syndrome, “torsades de pointes”, and ventricular fibrillation. Mosapride, another 5-HT4 agonist and Cinitapride, a 5-HT4, 5-HT1 and 5-HT2 antagonist, enhance GE with the above-mentioned risks and are only available in a few countries. Levosulpiride showing antidopaminergic activity in addition to 5-HT4 agonist activity, has the same prokinetic activity and adverse effects as cisapride, but, manifesting an effective antipsychotic property too, is above all used in psychiatry.
Also, Motilin agonists, such as macrolide antibiotics erythromycin, clarithromycin and azithromycin, endowed with a good prokinetic activity, show unwanted side effects, such as induction of cardiac arrhythmias, impairment of gastric accommodation, exposure to the risk of developing antibiotic resistant bacteria, and development of tachyphylaxis, which limits its use to a few weeks.
However, the future does look brighter, because newer agents targeting diverse gastric motor functions are appearing, such as novel 5-HT4agonists, ghrelin hormone agonists and the new acetyl-cholinesterase inhibitors. In fact, the novel 5-HT4 agonists, such as Prucalopride and Velusetrag, appear to be devoid of cardiac, vascular and nervous adverse effects and show a good prokinetic activity. The ghrelin receptor agonist, Relamorelin, stimulates gastric contractions, accelerating GE of solids and improves nausea, fullness, bloating and pain in patients with gastroparesis and type 2 diabetes.
The old acetyl-cholinesterase inhibitor, Neostigmine, which induces an irregular increase in gastroduodenal motility with accelerated GE by the parenteral way, is useful only in critically ill patients and may cause cardiac rhythm alterations. Vice versa, the new acetyl-cholinesterase inhibitor, Acotiamide, which is also an antagonist of presynaptic M1 and M2 muscarinic receptors, enhances both contractile and postprandial accommodation activities of the stomach and decreases dyspeptic symptoms, whereas Buspirone, a serotonergic 5-HT1A agonist, only improves postprandial accommodation and dyspeptic symptoms.
Antiemetics, prescribed only when the symptoms are dominated by nausea and vomiting, are represented by 5HT-3receptor antagonists, such as Granisetron and Ondansetron, which efficaciously fight nausea and vomiting in patients with gastroparesis, whereas Neurokinin NK1 antagonists, such as Aprepitant and, above all, Tradipitant, improve less effectively nausea through the increase of gastric postprandial accommodation, without affecting GE.
In addition, some medication-refractory patients may benefit from the emerging treatment of gastric neuromodulation[43]. Among the neuromodulators, Levosulpiride, already mentioned among prokinetics and generally used as anti-psychotic agents, may alleviate DG symptoms[22]. Among the antidepressants, Mirtazapine improves nausea, vomiting and appetite loss with its central adrenergic and serotonergic activities[51]. The new promising dopaminergic D2/3 antagonist, Trazpiroben, under development for the treatment of gastroparesis, designed to avoid adverse effects associated with metoclopramide and domperidone therapies, improves symptoms of postprandial fullness without evident prokinetic effects on GE[52], also when compared with placebo[53].
Finally, there are new emerging studies that, instead of stimulating the residual contractility of gastric musculature, try to restore its damages, by acting on the altered patho-physiological mechanisms in various ways: by controlling oxidative stress with hemin[54], by enhancing the recovery of neurons in the damaged myenteric plexus with benzalkonium chloride[55] and by favoring neurogenesis with exogenous brain-derived neurotrophic factors[56] and with exogenous recombinant human BDNF and neurotrophin-3[57]. In addition, TGFβR-1/ALK5 inhibitor RepSox induces enteric glia-to-neuron transition[58], while gastric electrical stimulation (GES) seems to increase the proliferation of the interstitial cells of Cajal[59].
The electrical, endoscopic and surgical treatments
For patient’s refractory to medical therapy, more invasive measures can be used, such as GES, surgical and non-surgical endoscopic treatments and open surgery.
GES consists of a series of electrical stimuli sent by a subcutaneously placed pulse generator to two leads placed in the muscularis propria of the gastric greater curvature about 10 cm proximal to the pylorus. This technique improves gastroparesis symptoms, such as vomiting, with an unknown mechanism[60], but some authors[61] assert that GES activates the vagal afferent pathways to influence the central control mechanisms for nausea and vomiting. With regard to the effect on GE, for some investigators[62,63] GES improves both symptoms and GE, whereas for others[22,64] there is only a significant improvement in symptoms and no effect on GE.
The non-surgical endoscopic treatments comprise endoscopic pyloric botulinum toxin infiltrations and pyloric BDs, which Wellington et al[65] used alternatively up to 3 treatments in 33 patients with gastroparesis obtaining significant GE and symptom improvement in 78% of them. Another more recent similar article of Noar and Khan[66] seems to open new perspectives for this treatment. In fact, in a series of 30 patients with gastroparesis and pyloric dysfunction, electrogastrogram, solid-phase nuclear GE and various kinds of symptom scores were carried out. The patients were subdivided into two groups on the basis of normal, or not normal, gastric electric activity (GEA) and were subjected to pyloric BD. The group with normal GEA showed, not only better symptom scores, but also a significant (P < 0.001) improvement in GE, in contrast with the other group. The most interesting result of this study is that the Automatic Intelligence-derived GMA threshold of 0.59 predicted positive pyloric BD outcomes at 10-12months with sensitivity 96%, specificity 75%, and 93% correct classification. The ultimate significance of this latter research, which needs to be confirmed with controlled trials, lies in the concept that treatment with BD for pylorospasm could be effective only in patients whose electrogastrogram is normal indicating a still good performance of ICC. Hence, pyloric BD could be used with good results immediately after early diagnosis of DG, when the delayed GE is due to pylorospasm, as above suggested. Therefore, it would be worthwhile to conduct a study in this direction.
Certainly, more effective in full-blown DG, is the more invasive treatment with gastric per oral endoscopic pyloromyotomy, which obtained positive results between 56% and 80% of patients treated, with very low frequency of severe adverse events[67] and with a significant improvement of both symptoms and GE during midterm follow-up of 18 months[68].
Finally, in patients who remain refractory to any of the above mentioned treatments, the placement of a feeding jejunostomy and/or a venting gastrostomy may be considered the last resort before gastric resection with Roux-en-Y anastomosis[69].
Concluding remarks
I hope I have convinced everyone who deals with diabetic patients from general practitioners to specialists, such as diabetologists and gastroenterologists, that it is very important to make the diagnosis of DG as soon as possible during its natural history.
The early diagnosis could allow a possible therapeutic intervention on enteric neuropathy with the emerging treatments aimed, at best, to obtain the regression of the initial nervous alterations and, at least, to slow down its worsening prior to evolution into full-blown disease with severe and threatening complications and need of heavy medical and surgical treatments above described.
As the identification of specific biomarkers in blood or stool samples, which could be useful for the early detection of enteric neuropathy and would allow for a rapid and precise diagnosis of gastroparesis, is unfortunately still unavailable. The discovery of an initial delay in GE by means of an appropriate test appears the most reliable tell-tale for singling out the onset of this disease.
To achieve this goal, it is necessary to subject the diabetic patients at risk of developing gastroparesis following the criteria above described to an annual GE test under the aforementioned guidelines. If the GE results delayed and the postprandial BSGM test is altered, the diagnosis of gastroparesis is done, but, if the BSGM test is normal, a high-resolution antro-pyloric-duodenal manometry or, at least, an EndoFLIP device test should be carried out to look for the presence of pylorospasm, with consequent therapeutic interventions, as described above.
Once the diagnosis of DG has been reached, an appropriate diet for gastric dysmotility, a wise use of safe novel prokinetic drugs, in addition to a strict control of glycemic levels must be done.
In the meantime, novel targets concerning new areas of research, such as macrophage/inflammatory function, oxidative stress, and neurogenesis, aimed to restore the ENS damages are emerging and are about to bear their first results.
