AGA Clinical Practice Update on GI Manifestations and Autonomic or Immune Dysfunction in Hypermobile Ehlers-Danlos Syndrome: Expert Review 2025 Harris

Abstract

Description
The purpose of this Clinical Practice Update Expert Review is to describe key principles in the evaluation and management of patients with disorders of gut-brain interaction (DGBI) and hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSDs) with coexisting postural orthostatic tachycardia syndrome (POTS) and/or mast cell activation syndrome (MCAS).

Methods
This expert review/commentary was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations.

Best Practice Advice 1
Clinicians should be aware of the observed associations between hEDS or HSDs and POTS and/or MCAS and their overlapping gastrointestinal (GI) manifestations; while theoretical explanations exist, experimental evidence of the biological mechanisms that explain relationships is limited and evolving.

Best Practice Advice 2
Testing for POTS/MCAS should be targeted to patients presenting with clinical manifestations of POTS/MCAS, but universal testing for POTS/MCAS in all patients with hEDS/HSDs is not supported by the current evidence.

Best Practice Advice 3
Gastroenterologists seeing patients with DGBI should inquire about joint hypermobility and strongly consider incorporating the Beighton score for assessing joint hypermobility into their practice as a screening tool; if the screen is positive, gastroenterologists may consider applying 2017 diagnostic criteria to diagnose hEDS (https://www.ehlers-danlos.com/wp-content/uploads/2017/05/hEDS-Dx-Criteria-checklist-1.pdf) or offer appropriate referral to a specialist where resources are available.

Best Practice Advice 4
Testing for POTS through postural vital signs (eg, symptomatic increase in heart rate of 30 beats/min or more with 10 minutes of standing during an active stand or head-up tilt table test in the absence of orthostasis) and referral to specialty practices (eg, cardiology or neurology) for autonomic testing should be considered in patients with hEDS/HSDs and refractory GI symptoms who also report orthostatic intolerance after exclusion of medication side effects and appropriate lifestyle or behavioral modifications (eg, adequate hydration and physical exercise) have been attempted but is not required for all patients with hEDS/HSDs who report GI symptoms alone.

Best Practice Advice 5
In patients presenting to gastroenterology providers, testing for mast cell disorders including MCAS should be considered in patients with hEDS/HSDs and DGBI who also present with episodic symptoms that suggest a more generalized mast cell disorder (eg, visceral and somatic pain, pruritus, flushing, sweating, urticaria, angioedema, wheezing, tachycardia, abdominal cramping, vomiting, nausea, diarrhea, urogynecological and neurological complaints) involving 2 or more physiological systems (eg, cutaneous, GI, cardiac, respiratory, and neuropsychiatric), but current data do not support the use of these tests for routine evaluation of GI symptoms in all patients with hEDS/HSDs without clinical or laboratory evidence of a primary or secondary mast cell disorder.

Best Practice Advice 6
If MCAS is suspected, diagnostic testing with serum tryptase levels collected at baseline and 1–4 hours following symptom flares may be considered by the gastroenterologist; increases of 20% above baseline plus 2 ng/mL are necessary to demonstrate evidence of mast cell activation.

Best Practice Advice 7
If a diagnosis of MCAS is supported through clinical and/or laboratory features, patients should be referred to an allergy specialist or mast cell disease research center where additional testing (eg, urinary N-methylhistamine, leukotriene E4, 11β-prostaglandin F2) may be performed.

Best Practice Advice 8
Diagnostic evaluation of GI symptoms consistent with DGBI in patients with hEDS/HSDs and comorbid POTS and/or MCAS should follow a similar approach to the evaluation of DGBI as in the general population including the use of a positive symptom-based diagnostic strategy and limited noninvasive testing.

Best Practice Advice 9
Testing for celiac disease may be considered earlier in the diagnostic evaluation of patients with hEDS/HSDs who report a variety of GI symptoms and not only limited to those with diarrhea. There is insufficient research to support routine testing for disaccharidase deficiencies or other diet-mediated mechanisms as causes of GI symptoms in hEDS/HSDs.

Best Practice Advice 10
Diagnostic testing for functional defecation disorders with anorectal manometry, balloon expulsion test, or defecography should be considered in patients with hEDS/HSDs and lower GI symptoms such as incomplete evacuation given the high prevalence of pelvic floor dysfunction, especially rectal hyposensitivity, in this population.

Best Practice Advice 11
In patients with hEDS/HSDs and comorbid POTS who report chronic upper GI symptoms, timely diagnostic testing of gastric motor functions (eg, measurement of gastric emptying and/or accommodation) should be considered after appropriate exclusion of anatomical and structural diseases, as abnormal gastric emptying may be more common than in the general population.

Best Practice Advice 12
Medical management of GI symptoms in hEDS/HSDs and POTS/MCAS should focus on treating the most prominent GI symptoms and abnormal GI function test results. In addition to general DGBIs and GI motility disorder treatment, management should also include treating any symptoms attributable to POTS and/or MCAS.

Best Practice Advice 13
Treatment of POTS may include increasing fluid and salt intake, exercise training, and use of compression garments. Special pharmacological treatments for volume expansion, heart rate control, and vasoconstriction with integrated care from multiple specialties (eg, cardiology, neurology) should be considered in patients who do not respond to conservative lifestyle measures.

Best Practice Advice 14
When MCAS is suspected, patients can benefit from treatment with histamine receptor antagonists and/or mast cell stabilizers, in addition to avoiding triggers such as certain foods, alcohol, strong smells, temperature changes, mechanical stimuli (eg, friction), emotional distress (eg, pollen, mold), or specific medications (eg, opioids, nonsteroidal anti-inflammatory agents, iodinated contrast).

Best Practice Advice 15
Besides general nutritional support, special diets including a gastroparesis diet (ie, small particle diet) and various elimination diets (eg, low fermentable carbohydrates, gluten- or dairy-free, low-histamine diets) can be considered for improving GI symptoms. Dietary interventions should be delivered with appropriate nutritional counseling or guidance to avoid the pitfalls of restrictive eating.

Best Practice Advice 16
Management of chronic GI symptoms in patients with hEDS/HSDs who do not exhibit symptoms consistent with POTS or MCAS should align with existing approaches to management of DGBI and GI motility disorders in the general population, including integrated multidisciplinary care involving multiple specialties, where appropriate (eg, cardiology, rheumatology, dietician, psychology).

Paywall

 

I get the impression that gastroenterologists are now completely clueless.
There does not seem to be a glimmer of evidence anywhere here.

 

When still working as a clinician ‘best practice’ seemed a very useful concept, however now I am much more skeptical.

I suspect for sharing ‘best practice’ to provide useful clinical insights we also need a good associated established scientific research based knowledge pool, that is talking about the best ways to implement what has already been independently verified, however using ‘best practice’ as a substitute for good experimental research has real dangers as can be seen in relation to GET/CBT for ME/CFS.

 

It is increasingly my perception that the whole ethos of medicine in Western countries has changed - especially in the USA but also the UK (I am less in a position to judge for Europe). In the 1970s US medical literature was high quality. The textbooks were far more rigorous than in the UK. American medicine seemed to be genuinely evidence and science based and rigour was taken as a gauge of 'street cred'. Since about 1995 US academic medicine has taken a dive, with far lower productivity than Europe. But we have also seen a huge expansion in things like 'Colleges of Osteopathic Medicine' which seem to be essentially also-ran medical schools for those who don't mind being quacks in order to make a living. The NIH used to have a reputation for excellence. Recently it seems to have been even more inward-looking and unproductive than MRC. And of course the WHO decided to 'put Traditional Chineses Medicine on the same footing as Western Medicine'. It seems to me that capitalism has bought out intellectual rigour - other than of course on S4ME.

And yes, in the Norwegian thread they are also talking of Richard Feynman turning in his grave! In my other field I sense that physics and neuroscience may have gone the same way