Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features

Abstract

Background: The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis.

Methods: Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models.

Results: Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206⁺ macrophages in both groups compared with obese controls.

Conclusions: A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. CLINICALTRIALS.

Gov identifier: NCT00398801, NCT01696747.

Keywords: Chronic Nausea; Enteric Nervous System; Functional Dyspepsia; Gastric Emptying; Gastroparesis.

Figure 1:

79 patients with gastroparesis (Gp) and 22 patients with Gp symptoms, normal gastric retention and functional dyspepsia (FD) using the Rome III classification at enrollment are compared by 4-hour % gastric retention and severity of the total GCSI score (0–5) at baseline and at 48-weeks of follow-up. Boxplots and dot plot distributions of total GCSI (blue) and % gastric retention (maroon) are displayed. Each dot represents a patient’s values. (A): 79 patients with Gp at baseline had normal gastric retention at 48-weeks (Gp converters) and (B): 22 patients without delayed retention (FD) at baseline had delayed gastric emptying at 48-weeks (FD converters). Total GCSI remained similar at both time points. Scatterplots and fitted regression lines at baseline (maroon, pink regression line) and 48-weeks (blue) are displayed. (C) Gp converters: y=2.53 + 0.009*x, r=0.16 at baseline and y=2.20 + 0.05*x, r=0.13 at 48-weeks, and (D) FD converters: y=3.28 – 0.001*x, r=−0.01 at baseline and y=2.94 – 0.002*x, -r=.07, where y=GCSI score and x=% gastric retention.

Figure 2:

Three histologic biomarkers were analyzed over 3 subgroups, each with 9 non-diabetic patients’ samples per group: Controls, functional dyspepsia (FD) and normal emptying and gastroparesis (Gp). The biomarkers were determined using stained stomach tissue slides, with multiple counts per circular field under high-powered focus (hpf) per patient. The number of counts per patient varied by the histological biomarker and patient. Each figure displays individual patient’s mean count (dots) and the adjusted mean count per subgroup (horizontal line). P (2-sided) determined using a mixed multiple linear regression model regressing each patient’s biomarker counts on the 3-category subgroup, accounting for the repeated measures per patient. Top - figure: (A) Interstitial Cells of Cajal (expressing c-Kit) in circular muscle showing decreased cell count numbers in FD and gastroparesis in a linear trend from controls (P≤.0001), with no difference seen between the two syndromes (B) CD206 (myenteric plexus) positive macrophage counts showing decreased numbers in both FD and gastroparesis (P≤.0009), with no difference seen between the two syndromes (C) Neuronal counts (as measured by Protein Gene Product 9.5 (PGP9.5) staining) in circular muscle showed no difference between any of the three groups (P=.39). Bottom - image: Images of histological changes in control patients and patients with functional dyspepsia (FD) and idiopathic gastroparesis. (A): c-Kit (circular muscle) showing decreased immunoreactivity in FD and idiopathic gastroparesis (arrows (horizontal lines) indicate interstitial cells of Cajal (ICC) with slender bodies and 2–3 processes; arrowheads indicate mast cells with larger, rounded bodies and no processes. (B): CD206 staining of myenteric plexi showing decreased immunoreactivity in both FD and gastroparesis. (C): PGP9.5 staining for neurons. Images obtained at 20x magnification (scale=20 μm).