Understanding and Treating Hypermobile Ehlers-Danlos Syndrome (hEDS)

Hypermobile Ehlers-Danlos Syndrome (hEDS) presents a unique challenge for clinicians, given its heterogeneity and lack of a definitive genetic marker. Unlike other EDS subtypes, hEDS is best conceptualized as a multisystem protein metabolism disorder, rather than simply a collection of mechanical symptoms tied to joint hypermobility. This approach allows for a more integrated and mechanistic understanding, which is essential for comprehensive management.

Reconceptualizing hEDS: Beyond Mechanical Instability

hEDS is characterized by a constellation of symptoms—including joint instability, pain, dysautonomia, gastrointestinal dysfunction, and immune dysregulation—that cannot be sufficiently explained by mechanical factors alone. The presentation of multiple overlapping syndromes in individual patients (such as POTS, MCAS, autonomic dysfunction, and chronic pain syndromes) highlights a common and systemic pathophysiological substrate.

 Recent research supports the notion that hEDS is fundamentally a disturbance in protein metabolism. Specifically, evidence points toward impaired connective tissue protein synthesis and increased breakdown of extracellular matrix components mediated by matrix metalloproteinases (MMPs). These enzymatic imbalances result in both tissue fragility and chronic, low-grade inflammation.

Kernel of the Pathophysiology: Protein Metabolism and Matrix Breakdown

Clinicians should note that, in hEDS, the core dysfunction appears to be twofold: suboptimal synthesis of connective tissue proteins and upregulated matrix degradation through hyperactive MMPs. This scenario is supported by transcriptomic data from dermal fibroblasts, analytically linking hEDS and hypermobility spectrum disorders as disorders of extracellular matrix homeostasis.

The downstream physiological consequences are broad:

• Mechanical instability: Manifested as joint hypermobility, vascular laxity, and gastrointestinal dysmotility.

• Neuroimmune activation: Chronic matrix breakdown generates DAMPs (danger-associated molecular patterns), perpetuating local and systemic inflammation. This in turn activates mast cells, autoimmune pathways, and microglial cells, potentially driving central sensitization and the development of secondary pain syndromes.

Clinical Management: A Mechanistic, System-Based Approach

Instead of a purely symptom-driven strategy, clinicians should stratify hEDS into predominant “buckets” for targeted management: mechanical/structural, immune/inflammatory, and central nervous system sensitization.

Nutritional Interventions: Prioritize Protein Intake

Optimal protein intake is critical, as hEDS patients often have increased protein turnover and poor tissue repair reserve. For unwell individuals, an intake of at least 1.2g/kg/day is recommended, with higher targets (1.6–2.0g/kg/day) for those seeking to rehabilitate muscle mass or withstand ongoing inflammation. Insufficient intake is common, especially among female patients and those with GI comorbidities. Collagen peptides, hydrolyzed protein supplements, and easily digestible, protein-dense foods should be considered where tolerance is an issue.

Pharmacologic and Lifestyle Considerations

• Avoidance of MMP-inducing agents: Fluoroquinolone antibiotics (e.g., ciprofloxacin) should be avoided due to their established role in upregulating MMP activity.

• Zinc supplementation: As MMPs are zinc-dependent, excessive zinc intake can exacerbate matrix degradation and should be minimized or avoided.

• Vegan or exclusively plant-based diets: These increase the risk of protein deficiency due to lower bioavailability and should be carefully managed if undertaken, with attention to bioequivalent dosing and absorption.

Symptom Cluster Management

• Mechanical/joint instability: Targeted rehabilitation and individual joint protection strategies remain foundational.

• Cardiovascular/autonomic symptoms (e.g., POTS): Aggressive hydration (targeting ~3L/day), appropriate sodium supplementation, and the addition of protein to fluids can ameliorate symptoms.

• Gastrointestinal dysfunction: Employ lower-residue, higher-protein diets, and consider splitting protein intake across multiple small meals to minimize intolerance.

Addressing “Burning Fires” Strategically

Prioritize intervention in the most dominant clinical domain—whether immune dysregulation, mast cell activation, gastrointestinal symptoms, or pain/central sensitization. Manage each as a distinct but interrelated pathophysiological driver. Treating the most destabilizing element often yields the greatest improvement in overall symptom burden.

Prevention and Prognosis

While there is not yet definitive clinical trial evidence, the hypothesis that early and sustained optimization of protein intake and management of metabolic drivers could mitigate progression, particularly in pediatric or early-diagnosed cases, is compelling. Clinicians should recognize the progressive nature of hEDS as a cumulative process, with opportunity for upstream intervention and potentially primary prevention of secondary complications.

Our Takeaway For You

As clinicians, we must adopt a holistic and mechanistic perspective when evaluating and managing patients with hEDS. Recognizing the disorder as a chronic protein metabolism dysfunction with multisystem impact allows for more targeted and rational interventions. Early attention to nutritional adequacy and avoidance of environmental exacerbants, coupled with a stratified approach to comorbidities, is likely to improve outcomes for this complex patient population.

For more insight and practical advice, tune in to episode 30 of It’s Not in Your Head Podcast.