Spectrum of Interstitial Cell of Cajal Deficits in Chronic Gastroduodenal Disorders: Systematic Review and Meta-Analysis

Background and Aims:Chronic neurogastroduodenal disorders are heterogeneous and thought to lie on a spectrum of disease encompassing both sensory and neuromuscular pathologies. Abnormalities of interstitial cells of Cajal (ICC), a subset of which generate pacemaker signals and subsequently motility, have been implicated in their pathophysiology. We systematically reviewed the literature to pool ICC deficits observed in chronic neurogastroduodenal disorders.Methods:Studies quantifying gastric ICC from the corpus or antrum, in adult patients with gastroparesis, functional dyspepsia (FD) or chronic nausea and vomiting syndromes (CNVS) were analysed (PROSPERO: CRD42024613226). MEDLINE, Embase and CENTRAL databases were searched systematically. Random effects meta-analyses were used to compare ICC counts by disorder group with subgroup analysis by quantification methodology.Results:2158 studies were screened and 22 included. Comparative studies (n=12) showed patients with chronic neurogastroduodenal disorders (n=167 with gastroparesis, n=19 with FD±CNVS) had lower ICC counts than non-diabetic controls (n=130); standardised mean difference -1.58, 95% confidence interval -2.09 to -1.07, p<0.0001, with more severe deficits in gastroparesis compared to FD±CNVS (SMD -0.44, p=0.048). A spectrum of ICC deficits was evident in a subgroup of studies using gold-standard methods with c-KIT antibody and DAPI-stained nuclei confirmation (7 studies, 246 patients: mean ICC counts 2.29 in gastroparesis vs 3.49 in FD±CNVS, and 5.27 in controls; p<0.001 all comparisons). Most studies were at high risk of bias (n=21).Conclusion:Marked depletion of ICC is a consistent finding in neurogastroduodenal disorders. A spectrum of disease is revealed, with greater depletion associated with delayed emptying. Techniques for clinically defining ICC-driven gastric neuromuscular dysfunction should be prioritized.