POTS Comorbidities- by Functional Domain

Dr Graham Exelby May 2025

Abstract:

This paper provides a structured overview of comorbid conditions observed in clinical POTS practice, grouped by functional domain. It serves as a bridge between clinical observation and mechanistic understanding and lays the foundation for individual domain-specific reviews.

Introduction:

Postural Orthostatic Tachycardia Syndrome (POTS) is a complex, multisystem disorder that arises from intersecting dysfunctions in autonomic regulation, immune signalling, vascular integrity, and cellular metabolism. Rather than a singular disease entity, POTS reflects a spectrum of physiological disarray often triggered by infection, trauma, or genetic predisposition.

Comorbidities in POTS are not incidental—they emerge through shared mechanisms such as chronic hypoperfusion, mast cell activation, mitochondrial dysfunction, and neuroimmune sensitization. This document provides a structured overview of these comorbidities, organized by functional domain, to assist clinicians in pattern recognition and multidisciplinary management. Each category serves as a scaffold for deeper mechanistic and clinical exploration in linked domain-specific papers.

Comorbidity Categories by Functional Domain

1.     Neurovascular and Perfusion-Linked Comorbidities

POTS is fundamentally a disorder of perfusion (hypoxia), often compounded by impaired neurovascular regulation and cerebral autoregulation. These comorbidities reflect chronic brainstem hypoperfusion, baroreceptor dysregulation, and altered cerebrovascular flow, frequently manifesting in overlapping syndromes such as migraine and central sensitization.

• Chronic Fatigue Syndrome / ME

• Brainstem Hypoperfusion

• Intracranial Hypertension (IIH)

• Migraine

• Central Sensitization

• Cerebral Hyperintensities (WMHs)

• Sleep Apnoea (central and obstructive)

• Restless Leg Syndrome (RLS)

2.     Immune-Mediated and Autoimmune Comorbidities Immune activation

Immune activation, particularly via TLR4, RAGE, and mast cell pathways—forms a central pillar in POTS pathophysiology. Many patients meet diagnostic criteria for autoimmune or post-infectious syndromes. This section includes classic autoimmune diseases as well as syndromes of chronic immune dysregulation.

• Mast Cell Activation Syndrome (MCAS)

• Autoimmune Thyroiditis (Hashimoto's)

• SLE

• Sjögren’s Syndrome

• Behçet’s Disease

• Lichen Sclerosis

• Long COVID / Post-Vaccine Syndrome

• Lyme and Tick-borne Illnesses

3.     Metabolic and Mitochondrial Disorders 

Many POTS patients exhibit bioenergetic collapse due to impaired mitochondrial function and oxidative stress. Dysfunctional PDH activity, amino acid depletion, and impaired redox cycling are frequently observed, especially post-viral or in genetically predisposed individuals. These metabolic deficits compromise orthostatic resilience, enhance post-exertional malaise (PEM), and contribute to cognitive and muscular fatigue.

• Mitochondrial Dysfunction (secondary to PDK activation or oxidative stress)

• Primary Mitochondrial Disease

• Non-Alcoholic Fatty Liver Disease (NAFLD)

• Hypoglycaemia / Glucose Dysregulation

4.     Mechanical and Structural Syndromes

Mechanical factors often compound autonomic dysfunction in POTS, particularly through cervical instability, vascular compression, and lymphatic obstruction. These structural contributors exacerbate brainstem hypoxia, vagal withdrawal, and mechanical irritation of autonomic plexuses. Many patients present with overlapping conditions that reflect hypermobility, fascial tension, and impaired venous return.

• Ehlers-Danlos Syndrome (EDS)

• Chiari Malformation

• Tethered Cord Syndrome

• Temporomandibular Joint (TMJ) Dysfunction

• Cervicothoracic and Lumbar Lymphatic Drainage Impairment

• Craniocervical Instability (CCI)

• Nutcracker Syndrome (Left Renal Vein Compression)

• May-Thurner Syndrome

• Thoracic Outlet Syndrome (TOS)

5.     Neurological, Psychiatric, and Cognitive Overlap

Neuropsychiatric comorbidities in POTS reflect both structural brain changes and neurochemical dysregulation arising from chronic hypoxia, immune priming, and excitatory–inhibitory imbalance. Emotional lability, executive dysfunction, and sensory hypersensitivities are common and often misunderstood. These conditions may be primary, secondary to chronic stress, or intrinsically linked to neuroimmune activation.

• ADHD

• Autism Spectrum Disorder (ASD)

• Functional Neurological Disorder (FND)

• Non-epileptiform Seizures / Myoclonic Jerks

• HPA Axis Dysfunction

• Anxiety Disorders

• Depression

• Sleep Dysregulation

6.     Gastrointestinal and Hepatic Dysfunction

Gastrointestinal symptoms are nearly universal in POTS, reflecting a complex interplay between autonomic dysmotility, mast cell activation, lymphatic stasis, and altered microbiota. These conditions may precede, accompany, or emerge secondary to the dysautonomia. Chronic venous and lymphatic congestion frequently impair portal drainage, leading to hepatic inflammation and metabolic compromise. Many of these disorders reflect barrier dysfunction at the gut–blood interface and often require multi-pronged therapeutic strategies.

• Irritable Bowel Syndrome (IBS)

• Gastroparesis

• Gastroesophageal Reflux Disease (GORD)

• Functional Dyspepsia

• Small Intestinal Bacterial Overgrowth (SIBO)

• Mesenteric Lymphatic Congestion

• Food Intolerances (including Histamine, Oxalate, FODMAP)

• Bile Acid Malabsorption

• Non-Alcoholic Fatty Liver Disease (NAFLD)

• Elevated Liver Enzymes secondary to congestion or mast cell infiltration

7.     Endocrine and Glucose Dysregulation

Hormonal dysregulation is frequently observed in POTS patients, driven by HPA axis suppression, hypothalamic dysfunction, and altered sympathetic tone. These endocrine perturbations can significantly influence vascular tone, energy homeostasis, and immune activation. Many endocrine findings remain subclinical but become functionally significant in the context of autonomic instability.  Blood glucose dysregulation is very common, but cannot yet be explained by traditional endocrine concepts.

• Adrenal Insufficiency (relative or absolute)

• Hypopituitarism

• HPA Axis dysfunction

• Dysregulated Cortisol Awakening Response

• Hypoglycaemia (fasting or reactive)

• Insulin Resistance

• Thyroid Axis Abnormalities (non-autoimmune)

• Menstrual Irregularities

• Polycystic Ovary Syndrome (PCOS)

• Vasopressin Dysregulation / Diabetes Insipidus

• Inappropriate ADH Secretion (SIADH)

8.     Urogenital and Pelvic Floor Dysfunction

The pelvic region is uniquely susceptible to both vascular congestion and autonomic dysregulation in POTS. Venous compression syndromes such as May-Thurner and Nutcracker syndrome often impair drainage from the pelvic basin, contributing to bladder and reproductive symptoms. Additionally, mast cell activation within urogenital tissues and pelvic fascial restriction may drive both nociceptive pain and visceral dysfunction. Many patients experience overlap with endometriosis, pelvic congestion syndrome, and interstitial cystitis, creating a complex therapeutic challenge.

• Interstitial Cystitis / Bladder Pain Syndrome

• Urinary Urgency / Retention / Frequency (Non-Infectious)

• Pelvic Congestion Syndrome

• Endometriosis

• Dysmenorrhea

• Vulvodynia / Vestibulodynia

• Dyspareunia

• Uterine Fibroids

• Pelvic Floor Dysfunction (tight or hypotonic)

• Prostatitis (non-bacterial / chronic pelvic pain syndrome)

9.     Dermatological and Peripheral Vascular Syndromes 

Cutaneous manifestations in POTS frequently reflect autonomic dysregulation, mast cell activation, and impaired microvascular control. Dysaesthesia, rashes, and livedo reticularis often accompany thermoregulatory instability. Local tissue perfusion defects can manifest visibly and symptomatically, serving as external clues to deeper systemic dysfunction.

• Raynaud’s Phenomenon

• Livedo Reticularis

• Erythromelalgia

• Dermographism

• Chronic Urticaria

• Chilblains / Pernio

• Petechiae and Easy Bruising

• Skin Hyperpigmentation or Hypopigmentation

• Peripheral Cyanosis

• Temperature Dysregulation (hands/feet)

10.  Mast Cell Activation Spectrum Disorders

Mast cell dysregulation is a central but often under-recognized contributor to the multisystem involvement seen in POTS. Beyond the classical presentations of allergy, mast cell activation (MCA) affects vascular tone, pain sensitivity, gastrointestinal motility, and blood-brain barrier integrity. Patients may exhibit systemic symptoms that overlap with allergic, autoimmune, and neuropsychiatric disorders. This section highlights core and overlapping MCA presentations that frequently co-occur with POTS.

• Mast Cell Activation Syndrome (MCAS)

• Histamine Intolerance

• Idiopathic Anaphylaxis

• Multiple Drug and Food Sensitivities

• Flushing / Pruritus / Urticaria

• Heat Intolerance / Dysautonomic Sweating

• Angioedema (non-IgE mediated)

• Neuropsychiatric Reactivity to Mast Cell Mediators

• Fascial and Connective Tissue Reactivity (including head/neck tension)

Conclusion:

Comorbidities in POTS are rarely siloed. Instead, they represent manifestations of broader systemic dysfunctions that converge on autonomic, immune, metabolic, and mechanical interfaces. The functional domain approach not only aids diagnostic clarity but also underscores the need for integrated, individualized care pathways.

Recognizing these patterns enables clinicians to anticipate disease trajectories, improve diagnostic efficiency, and personalize treatment strategies. Future domain-specific expansions will further refine the mechanisms, diagnostics, and therapeutics pertinent to each category, ultimately fostering a systems medicine approach to POTS and its associated syndromes.