Prevalence of Gastrointestinal, Cardiovascular, Autonomic and Allergic Manifestations in Hospitalized Patients With Ehlers-Danlos Syndrome

A Case-Control Study

Rachel S. Brooks; James Grady; Thomas W. Lowder; Svetlana Blitshteyn


Rheumatology. 2021;60(9):4272-4280. 

In This Article

Abstract and Introduction


Objective: Previous observations suggest an association between Ehlers-Danlos syndrome (EDS) and gastrointestinal (GI), cardiovascular, immune, and autonomic nervous system dysfunction. We sought to determine whether a hospital diagnosis of EDS is associated with a higher prevalence of these manifestations vs hospitalized patients without EDS. We also evaluated hospital outcomes.

Methods: A total of 6,021 cases and matched controls were acquired from the 2016 National Inpatient Sample. In total, 2,007 EDS patients were identified via ICD-10 code. After bivariate analyses, multivariate logistic regression models were used to adjust for potential confounders.

Results: GI conditions were found in 44% of EDS patients vs 18% of controls [odds ratio (OR) = 3.57, 95% CI: 3.17, 4.02, P < 0.0001], with irritable bowel syndrome, gastroparesis and coeliac disease strongly associated with EDS. Autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope and orthostatic hypotension was found in 20% of EDS patients vs 6% of controls (OR = 4.45, 95% CI: 3.71, 5.32, P < 0.0001). EDS patients were more likely to have food allergy (OR = 3.88, 95% CI: 2.65, 5.66, P < 0.0001) and cardiovascular complications such as mitral valve disorders, aortic aneurysm and dysrhythmias (OR = 6.16, 95% CI: 4.60, 8.23, P < 0.0001). These conditions remained highly associated with EDS after considering confounders. EDS patients were 76% more likely to have longer than average hospitalizations (OR = 1.76, 95% CI: 1.54, 2.02, P < 0.0001).

Conclusion: GI, cardiovascular, autonomic and allergic manifestations are significantly more prevalent in EDS patients compared with hospitalized patients without EDS. Physicians should consider EDS in patients with unexplained GI, cardiovascular, autonomic and allergic conditions and exercise precautions when treating EDS patients in a hospital setting.


Ehlers-Danlos syndrome (EDS) is a group of heritable, heterogeneous connective tissue disorders affecting skin, ligaments, joints, blood vessels and internal organs.[1] EDS affects ~1 in 5000 individuals, resulting from defects in collagen, the main structural component of connective tissue.[2] Mutations in various genes, including COL1A1, COL5A1, COL5A2, COL3A1, TNXB and FKBP14, alter collagen production, enzymes that modify collagen, or proteins affecting collagen fibrillogenesis and structure, causing fibril disorganization, abnormal bundle size or decreased collagen synthesis.[2,3] Clinical characteristics of EDS vary, ranging from skin fragility, skin hyperextensibility, joint hypermobility, excessive bruising and abnormal scarring, to life-threatening vascular complications, chronic joint pain and severe physical disability. EDS consists of 13 recognized subtypes with varying genetic causes and clinical features,[3] the most common being hypermobile EDS.[4] Many subtypes have significant symptom overlap. Previous studies suggest associations between EDS and gastrointestinal, cardiovascular, immune and autonomic nervous system dysfunction, but no large case-control studies have examined the prevalence of these conditions in hospitalized EDS patients to date.

Most studies reporting gastrointestinal abnormalities and autonomic dysfunction in EDS have used small sample sizes or observations from speciality clinics.[5–8] Case reports demonstrate associations between cardiovascular complications and EDS[9,10] and one study finding eosinophilic esophagitis in patients with hereditary connective tissue disorders has suggested a link between food allergies and EDS.[11] Because these associations have not been further examined, the true frequency and nature of these conditions in EDS remains unknown. The aim of this study was to provide a robust investigation of the connection between EDS and gastrointestinal (GI), cardiovascular, autonomic and allergic manifestations, offering a more comprehensive picture than presently available. We sought to determine whether a hospital diagnosis of EDS is associated with higher prevalence of these conditions compared with the general population by performing a case-control study of hospitalized patients. A secondary aim of this study was to evaluate hospital outcomes of EDS patients compared with non-EDS patients.