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Gastroparesis: A Dead-end Street After All?

2021; Elsevier BV; Volume: 160; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2021.02.042

1528-0012

Jan Tack, Jolien Schol, Michael Horowitz,

Pathogenesis and Treatment of Hiccups

See “Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features,” by Pasricha PJ, Grover M, Yates KP, et al; NIDDK/NIH GpCRC consortium, on page 2006.‘Would you tell me, please, which way I ought to go from here?, said Alice.’That depends a good deal on where you want to get to’ said the Cat.‘I don’t much care where’ said Alice.’Then it doesn’t matter which way you go’ said the Cat.‘As long as I get somewhere’ Alice added as an explanation.‘Oh you’re sure to do that’ said the Cat, ’if you only walk long enough’—From Alice in Wonderland (Lewis Carroll, 1857), a conversation between Alice and the Cheshire Cat. See “Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features,” by Pasricha PJ, Grover M, Yates KP, et al; NIDDK/NIH GpCRC consortium, on page 2006. Chronic symptoms of postprandial fullness, early satiation, epigastric pain, nausea, or vomiting affect 10% of adults.1Sperber A.D. Bangdiwala S.I. Drossman D.A. et al.Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study.Gastroenterology. 2021; 160: 99-114Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar In the majority of such individuals, endoscopy and routine laboratory tests are normal, implicating a functional disorder.2Stanghellini V. Talley N. Chan F. et al.Functional gastroduodenal disorders.Gastroenterology. 2016; 150: 1380-1392Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar The measurement of gastric emptying (GE) identifies a substantial subset with gastroparesis, which has been assumed to underlie symptoms and to represent the therapeutic target. The latter concept, although intuitively logical, has been challenged by the poor concordance of symptoms with the rate of GE, and between the effects of prokinetic drugs on GE and symptoms.3Stanghellini V. Tack J. Gastroparesis: separate entity or just a part of dyspepsia?.Gut. 2014; 63: 1972-1978Crossref PubMed Scopus (81) Google Scholar, 4Vijayvargiya P. Jameie-Oskooei S. Camilleri M. et al.Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-analysis.Gut. 2019; 68: 804-813Crossref PubMed Scopus (64) Google Scholar, 5Janssen P. Harris M.S. Jones M. et al.The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis.Am J Gastroenterol. 2013; 108: 1382-1391Crossref PubMed Scopus (150) Google Scholar, 6Tack J. Goelen N. Carbone F. et al.Letter to the editor: prokinetic effects and symptom relief in the pharmacotherapy of gastroparesis.Gastroenterology. 2020; 158: 1841-1842Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Gastroparesis Clinical Consortium was initiated in 2006, in part to address these inconsistencies.7Pasricha P.J. Grover M. Yates K.P. et al.NIDDK/NIH GpCRC consortium. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features.Gastroenterology. 2021; 160: 2006-2017Abstract Full Text Full Text PDF Scopus (18) Google Scholar In this issue of Gastroenterology, the consortium reports a 48-week prospective follow-up study of 944 patients, 720 with gastroparesis and 224 normal emptying.7Pasricha P.J. Grover M. Yates K.P. et al.NIDDK/NIH GpCRC consortium. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features.Gastroenterology. 2021; 160: 2006-2017Abstract Full Text Full Text PDF Scopus (18) Google Scholar In both groups symptom patterns were comparable at baseline and 48 weeks. Whether initially delayed or normal, GE was shown not to be stable over time, so that 41% of patients changed categories at 48 weeks; moreover, there was no relationship between symptom severity and GE. Irrespective of GE status, a histologic analysis of full-thickness biopsies, performed in a small subset of patients, demonstrated decreased numbers of interstitial cells of Cajal and myenteric macrophages with an anti-inflammatory role. The authors conclude that a GE test lacks reliability for identifying a patient group with a distinct clinical condition or outcome. Whether “gastroparesis is a distinct entity or simply a part of dyspepsia” was raised in a 2014 viewpoint.3Stanghellini V. Tack J. Gastroparesis: separate entity or just a part of dyspepsia?.Gut. 2014; 63: 1972-1978Crossref PubMed Scopus (81) Google Scholar The current study aligns the NIDDK Gastroparesis Clinical Consortium authors with this view; they state, “Functional dyspepsia (FD) and gastroparesis may be part of the same clinicopathological spectrum of gastric neuromuscular dysfunction.” This issue has major implications for clinical practice, disease classification, pathophysiologic research, and the development of novel therapies. Previous reports attest to the poor stability of GE measurements over time in this group and the weak, if any, relationship of symptoms with GE.3Stanghellini V. Tack J. Gastroparesis: separate entity or just a part of dyspepsia?.Gut. 2014; 63: 1972-1978Crossref PubMed Scopus (81) Google Scholar, 4Vijayvargiya P. Jameie-Oskooei S. Camilleri M. et al.Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-analysis.Gut. 2019; 68: 804-813Crossref PubMed Scopus (64) Google Scholar, 5Janssen P. Harris M.S. Jones M. et al.The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis.Am J Gastroenterol. 2013; 108: 1382-1391Crossref PubMed Scopus (150) Google Scholar, 6Tack J. Goelen N. Carbone F. et al.Letter to the editor: prokinetic effects and symptom relief in the pharmacotherapy of gastroparesis.Gastroenterology. 2020; 158: 1841-1842Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 7Pasricha P.J. Grover M. Yates K.P. et al.NIDDK/NIH GpCRC consortium. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features.Gastroenterology. 2021; 160: 2006-2017Abstract Full Text Full Text PDF Scopus (18) Google Scholar, 8Tougas G. Ying C. Luo D. et al.Tegaserod improves gastric emptying in patients with gastroparesis and dyspeptic symptoms.Gastroenterology. 2003; 124: A54Abstract Full Text PDF Google Scholar, 9Arts J. Caenepeel P. Verbeke K. et al.Influence of erythromycin on gastric emptying and meal related symptoms in functional dyspepsia with delayed gastric emptying.Gut. 2005; 54: 455-460Crossref PubMed Scopus (108) Google Scholar, 10Desai A. O'Connor M. Neja B. et al.Reproducibility of gastric emptying assessed with scintigraphy in patients with upper GI symptoms.Neurogastroenterol Motil. 2018; 30: e13365Crossref PubMed Scopus (18) Google Scholar The current study confirms these findings in a very large cohort closely followed prospectively. Is the implication that we should consider all patients with chronic gastroduodenal symptoms as having FD, cease measuring GE and manage them (if Helicobacter pylori is absent or eradicated) in a uniform treatment sequence of proton pump inhibitors, tricyclic antidepressants and prokinetics as third-line therapy, as proposed by the American College of Gastroenterology/American College of Gastroenterology consensus?11Moayyedi P. Lacy B.E. Andrews C.N. et al.ACG and CAG clinical guideline: management of dyspepsia.Am J Gastroenterol. 2017; 112: 988-1013Crossref PubMed Scopus (195) Google Scholar We believe that such an approach fails to adequately consider the variability of both the symptom pattern and the presumably heterogeneous nature of the underlying pathophysiology. It also ignores treatment approaches that have shown efficacy in gastroparesis, such as antiemetic agents.12Tack J. Camilleri M. New developments in the treatment of gastroparesis and functional dyspepsia.Curr Opin Pharmacol. 2018; 43: 111-117Crossref PubMed Scopus (37) Google Scholar,13Pasricha P.J. Yates K.P. Sarosiek I. et al.NIDDK Gastroparesis Clinical Research Consortium (GpCRC)Aprepitant has mixed effects on nausea and reduces other symptoms in patients with gastroparesis and related disorders.Gastroenterology. 2018; 154: 65-76.e11Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The Rome IV consensus identified early satiation, postprandial fullness, and epigastric pain or burning as cardinal symptoms of FD, and separated these from chronic nausea and vomiting disorders. The consensus also considered the measurement of GE useful in the latter group, given the reported association, albeit relatively weak, of symptoms of nausea and vomiting with delayed GE.2Stanghellini V. Talley N. Chan F. et al.Functional gastroduodenal disorders.Gastroenterology. 2016; 150: 1380-1392Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar,3Stanghellini V. Tack J. Gastroparesis: separate entity or just a part of dyspepsia?.Gut. 2014; 63: 1972-1978Crossref PubMed Scopus (81) Google Scholar The recent European consensuses on FD and on gastroparesis are in line with this concept.14Wauters L. Dickman R. Drug V. et al.the ESNM FD Consensus GroupUnited European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia.UEG J. 2021; (in press)Google Scholar,15Schol J. Wauters L. Dickman R. et al.the ESNM FD Consensus GroupUnited European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis.UEG J. 2021; (in press)Google Scholar The latter defines gastroparesis as a symptomatic condition associated with delayed GE in the absence of mechanical obstruction, with nausea and vomiting as cardinal symptoms, differentiating it from FD, and the management algorithm advocates early treatment with antiemetics and prokinetics.15Schol J. Wauters L. Dickman R. et al.the ESNM FD Consensus GroupUnited European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis.UEG J. 2021; (in press)Google Scholar Figure 1 illustrates the diagnostic concepts of these processes. The population in the NIDDK consortium article7Pasricha P.J. Grover M. Yates K.P. et al.NIDDK/NIH GpCRC consortium. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features.Gastroenterology. 2021; 160: 2006-2017Abstract Full Text Full Text PDF Scopus (18) Google Scholar is closest to this symptom profile and, hence, more reflective of patients with chronic nausea and vomiting, particularly in the subgroup in whom full-thickness biopsy was performed. The majority of patients in the Pasricha article had idiopathic disease, but approximately one-third were diabetics, with almost equal numbers of type 1 and type 2 patients.7Pasricha P.J. Grover M. Yates K.P. et al.NIDDK/NIH GpCRC consortium. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features.Gastroenterology. 2021; 160: 2006-2017Abstract Full Text Full Text PDF Scopus (18) Google Scholar The authors report that the clinical variables and their evolution did not differ between idiopathic and diabetic subgroups. However, the group that underwent full-thickness biopsy was exclusively idiopathic. It is conceivable that the cellular pathophysiological basis underlying gastroparesis and chronic nausea and vomiting in diabetes differs from that in idiopathic patients and is more likely to involve neuropathic and fibrotic abnormalities.16Grover M. Farrugia G. Stanghellini V. Gastroparesis: a turning point in understanding and treatment.Gut. 2019; 68: 2238-2250Crossref PubMed Scopus (47) Google Scholar In our opinion, the outcomes of the study by Pasricha et al7Pasricha P.J. Grover M. Yates K.P. et al.NIDDK/NIH GpCRC consortium. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features.Gastroenterology. 2021; 160: 2006-2017Abstract Full Text Full Text PDF Scopus (18) Google Scholar do not imply that we should stop performing GE studies in clinical practice. There are several reasons for a diagnostic test, including (1) establishing a specific diagnosis, (2) identifying the mechanism underlying symptoms, (3) determining the choice of treatment, and (4) predicting longer term outcomes. (1) In the past, the major rationale for GE measurement was the ability to specifically diagnose “gastroparesis,” an approach that the current study invalidates. (2) The observed poor link between symptoms and GE refutes the claim that the GE test identifies the mechanism underlying symptom generation. However, the demonstration of delayed GE supports the notion of “disordered gastric neuromuscular control,” which may well determine symptoms. (3) In many FD management algorithms, measurement of GE is not required to consider prescribing a prokinetic agent,11Moayyedi P. Lacy B.E. Andrews C.N. et al.ACG and CAG clinical guideline: management of dyspepsia.Am J Gastroenterol. 2017; 112: 988-1013Crossref PubMed Scopus (195) Google Scholar,14Wauters L. Dickman R. Drug V. et al.the ESNM FD Consensus GroupUnited European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia.UEG J. 2021; (in press)Google Scholar given that the result is not predictive of the outcome of prokinetic therapy.3Stanghellini V. Tack J. Gastroparesis: separate entity or just a part of dyspepsia?.Gut. 2014; 63: 1972-1978Crossref PubMed Scopus (81) Google Scholar,14Wauters L. Dickman R. Drug V. et al.the ESNM FD Consensus GroupUnited European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia.UEG J. 2021; (in press)Google Scholar In contrast, centrally acting neuromodulator therapy fails to benefit patients with delayed GE,17Talley N.J. Locke G.R. Saito Y.A. et al.Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study.Gastroenterology. 2015; 149: 340-349 e2Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar,18Parkman H.P. Van Natta M.L. Abell T.L. et al.Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial.JAMA. 2013; 310: 2640-2649Crossref PubMed Scopus (87) Google Scholar and the strong prokinetic agent prucalopride may improve upper gastrointestinal symptoms only in those with GE delay.19Carbone F. Van den Houte K. Clevers E. et al.Prucalopride in gastroparesis: a randomized placebo-controlled crossover study.Am J Gastroenterol. 2019; 114: 1265-1274Crossref PubMed Scopus (58) Google Scholar (4) Finally, although the current study failed to identify any difference in outcomes at 48 weeks, an earlier long-term follow-up study in FD found that delayed GE is a risk factor for symptom persistence.20Kindt S. Van Oudenhove L. Mispelon L. et al.Longitudinal and cross-sectional factors associated with long-term clinical course in functional dyspepsia: a 5-year follow-up study.Am J Gastroenterol. 2011; 106: 340-348Crossref PubMed Scopus (44) Google Scholar Uncertainties relating to disease entities and their characterizations have compromised scientific progress and contributed to the failure to deliver novel therapies for these patients. These provocative findings from Pasricha et al7Pasricha P.J. Grover M. Yates K.P. et al.NIDDK/NIH GpCRC consortium. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathological features.Gastroenterology. 2021; 160: 2006-2017Abstract Full Text Full Text PDF Scopus (18) Google Scholar call for a reassessment of the terminology and more precise categorization of conditions such as postprandial distress syndrome, epigastric pain syndrome, and chronic nausea/vomiting disorders,2Stanghellini V. Talley N. Chan F. et al.Functional gastroduodenal disorders.Gastroenterology. 2016; 150: 1380-1392Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar ideally by an international expert consensus. The creation or confirmation of these diagnostic categories should be accompanied by a reassessment of candidate pathophysiologic mechanisms (eg, gastric sensorimotor dysfunction, duodenal mucosal alterations). We believe that this path is the one most likely to lead to effective therapies for the many patients with chronic gastroduodenal symptoms.