The new guidelines aim to recognize and treat iron deficiency before it turns into anemia, and to prevent those with iron deficiency anemia from developing more severe iron deficiency anemia. Updated ferritin thresholds for diagnosis:

• 20 ng/mL or lower for young children

• 30 ng/mL or lower for adults and menstruating or pregnant individuals

• 50 ng/mL or lower for certain high-risk groups (heavy menstrual bleeding, anemia during pregnancy, restricted diets)

• For adults with inflammation, the guidelines recommend ferritin under 100 ng/mL or transferrin saturation under 20%- so what does this mean? If MCAS is an inflammatory condition, do we use this cutoff? Not exactly.

Iron Deficiency and Inflammation

Iron deficiency is easy to recognize when serum ferritin is low. But when it is normal or high there could still be iron deficiency if there are also certain states of inflammation. According to the new guidelines:

Anemia of Chronic Inflammation

“Inflammation” is a wide term. Different pathways of inflammation can affect ferritin stores differently. “Anemia of Chronic Inflammation” is a specific condition where inflammatory cytokines, chiefly IL-6, signal the liver to make hepcidin. Hepcidin blocks iron absorption from the gut and traps iron in macrophages and liver cells. The same cytokines also push ferritin production up directly. This results in normal or high ferritin without allowing the body to use it, creating a functional iron deficiency. In these cases we must rely on other iron markers like the transferrin saturation to determine the presence of a true iron deficiency.

Role of Systemic Inflammation in Anemia. Ganz T, N Engl J Med 2019;381:1148–57, Figure 2, Anemia of Inflammation. N Engl J Med. September 19, 2019.

In these guidelines, the section on inflammation shows the recommendations are based on very low certainty: The panel considered serum ferritin <100 ng/mL or transferrin saturation <20% to be accurate for the diagnosis of iron deficiency for many, but not necessarily all individuals in the setting of inflammation. The panel recognized that inflammation is a continuum and that dichotomous thresholds are limited in fully characterizing the spectrum and range of inflammation.

They further state: “anemia of inflammation may occur in individuals with inflammatory bowel disease, infectious disease, cancer, chronic kidney disease, heart failure, rheumatologic disorders, and other inflammatory disorders.” The key word in this sentence is “may.” While this is a general guidance, there are exceptions. In certain cancers like colon cancer and certain inflammatory conditions like celiac disease, the presenting symptom is actually iron deficiency with low ferritin because of where the inflammation is present (gut lining) leading to malabsorption or chronic GI bleeding.

So what does this mean for mast cell activation syndrome (MCAS)?

MCAS is an immune-mediated, inflammatory disorder, but it does not seem to cause elevated serum ferritin levels like we see in anemia of chronic inflammation.

Why not?

MCAS is episodic and defined by recurrent, paroxysmal release of chemical mediators that cause anaphylaxis-type symptoms across multiple organ systems. The dominant mediators for MCAS - histamine, tryptase, prostaglandins, leukotrienes- act rapidly and transiently on vascular, smooth muscle, and neural targets. Mast cells can release IL-6 and TNF-α, but there is no published evidence that episodic MCAS flares sustain the hepcidin and ferritin rise seen in anemia of chronic inflammation.

These guidelines of course did not single out threshold ferritin level at which MCAS patients would be considered iron replete. So these are some points I believe can be utilized when evaluating iron deficiency in patients with MCAS:

• MCAS is not known as a condition that raises ferritin levels

• In hEDS, POTS and MCAS, many already fall into a high risk group according to ASH:

  • heavy menstrual bleeding (presumably due to heparin, tryptase, and tPA release from mast cells or concurrent connective tissue disorders)

  • GI symptoms that can lead to restricted diets
    

Overall takeaway:

As a hematologist who is hEDS and MCAS-aware, my expert opinion is that these patients fit under the 'high risk' group, so a ferritin ≤50 ng/mL should be considered iron deficient. ASH does not address MCAS specifically.

Note: This is an expert medical opinion and not individual medical advice. Always speak to your physician about diagnosis and best treatments options for you.

Some content in this article was generated using artificial intelligence to illustrate and simplify explanation of scientific concepts. Images may not perfectly represent experimental workflows or scale. They are included to aid understanding rather than serve as primary scientific references.

Iron deficiency is the most common micronutrient deficiency worldwide. 1/3 adults, or approximately 2 billion people, are affected by this. Menstruating women, pregnant women, and infants/young children ages 6-11 months are the most affected groups. If left untreated, iron deficiency can progress to iron deficiency anemia.

Why is iron so important?

Iron is an essential micronutrient that is required for hemoglobin synthesis, red blood cell production, oxygen transport, mitochondrial energy production, neurotransmitter synthesis, and DNA replication. Our bodies have no active pathway to excrete iron, so iron deficiency occurs whenever iron intake, absorption, or recycling fails to keep up with losses or demand.

Symptoms can occur when iron deficiency develops, even before anemia sets in. These include fatigue, brain fog, irritability, poor concentration, headaches, restless legs syndrome, and pica (craving non-food substances, usually ice). This can progress into pallor, exercise intolerance, and exertional dyspnea (difficulty breathing when exerting energy).

The new guidelines aim to recognize and treat iron deficiency before it turns into anemia, and to prevent those with iron deficiency anemia from developing more severe iron deficiency anemia. In the past, lower stored forms of iron were considered sufficient, but it is evident that those lower numbers were still resulting in iron deficiency symptoms and all too often lowering further into iron deficiency anemia. For nearly every demographic, ASH now recommends a lower threshold at which to consider someone iron deficient.

How do you test for low iron?

The best measure of stored iron is the serum ferritin level. A low serum ferritin is always indicative of iron deficiency.

“Serum ferritin is widely available, commonly assessed, and considered the best indirect measure of total body iron stores, the panel prioritized this test in considering diagnostic questions. Serum ferritin is an acute phase reactant (raises in some states of inflammation) and is ideally tested during an individual’s baseline state of health. In healthy individuals without evidence of acute infection or chronic disease, serum ferritin is an accurate marker of iron status, and when low is diagnostic of iron deficiency.”

The new guidelines introduce updated ferritin thresholds for diagnosis:

▪️ 20 ng/mL or lower for young children
▪️ 30 ng/mL or lower for adults and menstruating or pregnant individuals
▪️ ️50 ng/mL or lower for certain high-risk groups (heavy menstrual bleeding, anemia during pregnancy, restricted diets)
▪️ For adults with inflammation, the guidelines recommend ferritin under 100 ng/mL or transferrin saturation under 20%

Honestly, hematologists have been utilizing these thresholds for some time now. I can’t tell you how many pregnant patients we see at the last minute because ferritin levels weren’t checked until they became anemic in their third trimester, then we rush to get them IV iron so they won’t need a blood transfusion at the time of delivery. Currently the American College of Obstetricians and Gynecologists (ACOG) does not mandate checking ferritin levels in pregnancy, so the hope is that this will change and pregnant patients will be screened earlier.

The Guidelines on Pregnancy:
ACOG does not currently recommend routine screening for iron deficiency during pregnancy. However, a body of evidence demonstrates the pervasiveness of iron deficiency (defined as serum ferritin <30 ng/mL) in pregnancy, irrespective of the presence or absence of anemia. In addition to impacting maternal outcomes, iron deficiency has potential negative impacts on the developing fetus. The use of hemoglobin and mean corpuscular volume (MCV) as surrogates for iron sufficiency is inaccurate, and literature demonstrates positive effects of early iron repletion in non-anemic pregnant individuals. Based on the above, the panel believes it is reasonable to screen for iron deficiency by checking serum ferritin in all pregnant individuals as well as other high-risk populations, with or without concomitant anemia

Iron Deficiency and Inflammation

Iron deficiency is easy to recognize when serum ferritin is low. But when it is normal or high there could still be iron deficiency if there are also certain states of inflammation.

In many states of inflammation, the body turns to a more functional iron deficiency by hiding away ferritin and not allowing it to incorporate into cells. This is called anemia of chronic inflammation/chronic disease, an inflammation-driven iron sequestration and suppressed erythropoiesis (RBC production). Inflammatory cytokines—particularly IL-6—drive liver hepcidin production, which degrades ferroportin and traps iron in macrophages while upregulating iron stores (high ferritin, low transferrin saturation). Ferritin is induced by cytokines such as TNF-α. The elevated ferritin reflects continuous cytokine signaling over weeks to months.

So more simply put, ferritin is an acute phase reactant, which means that it can be falsely elevated or normalized in acute or chronic inflammatory states, even when stores are truly depleted. This is when transferrin saturation (Tsat) comes into play. Tsat is a measure of how saturated iron receptors are. At a normal to high levels, it shows that the body has enough iron it is utilizing properly. At low levels (<20%), even when ferritin is normal or high, it is concerning for a functional iron deficiency.

Role of Systemic Inflammation in Anemia. Anemia of Inflammation. N Engl J Med. September 19, 2019.

The new guidelines define diagnosis of iron deficiency in adults with inflammation as the following:

“Inflammation” is a wide term. Different pathways of inflammation can affect ferritin stores differently. You can see that in these guidelines, the section on inflammation shows the recommendations are based on very low certainty. They state: “anemia of inflammation may occur in individuals with inflammatory bowel disease, infectious disease, cancer, chronic kidney disease, heart failure, rheumatologic disorders, and other inflammatory disorders.” The key word in this sentence is “may.” While this is a general guidance, there are exceptions. In certain cancers like colon cancer and certain inflammatory conditions like celiac disease, the presenting symptom is actually iron deficiency with low ferritin. Much of this has to do with where the inflammation is present (gut lining) leading to malabsorption, or chronic GI bleeding.

Per the guidelines: The panel considered serum ferritin <100 ng/mL or transferrin saturation <20% to be accurate for the diagnosis of iron deficiency for many, but not necessarily all individuals in the setting of inflammation. The panel recognized that inflammation is a continuum and that dichotomous thresholds are limited in fully characterizing the spectrum and range of inflammation. Regardless, thresholds for diagnostic and treatment guidance were judged to be of moderate benefit to patients.

Treating Iron Deficiency

The overall goal of these new guidelines is to acknowledge that symptoms can develop with iron deficiency even before anemia develops and to treat to both improve symptoms and prevent the development or worsening of anemia.

Oral iron is typically first-line therapy. It is recommended to take oral iron (generally ferrous sulfate 325mg) in the morning on an empty stomach, with a vitamin C source, and to avoid coffee/tea/dairy/calcium for at least an hour in order to maximize absorption and minimize GI side effects. No single ferrous salt (sulfate, fumarate, gluconate) is superior in efficacy or tolerability; ferrous salts are preferred over ferric salts for better bioavailability. Lactoferrin is a multifunctional iron binding-glycoprotein found in milk (especially colostrum) and oral bovine lactoferrin has been studied as an alternative or adjunct to ferrous salts, with the main theoretical advantages being fewer GI side effects and anti-inflammatory/hepcidin-lowering effects. The evidence for this, however, is conflicting.

Intravenous iron is indicated for patients with oral iron intolerance, poor absorption (celiac disease, post–bariatric surgical procedure), chronic inflammatory conditions (CKD, HF, IBD, cancer), ongoing blood loss, and during the second and third trimesters of pregnancy. Blood transfusions are only indicated for Hb <7.0 or symptomatic anemia with Hb <8.0.

All IV iron formulations have the same underlying structure of a carbohydrate shell surrounding an iron core. The shell stabilizes the iron and limits its release into plasma.

Common IV iron formulations include:

• iron sucrose (Venofer)

• ferric gluconate (Ferrlecit)

• low molecular weight iron dextran (INFeD)

• ferumoxytol (Feraheme)

• ferric carboxymaltose (Injectafer)

• ferric derisomaltose (Monoferric)

IV iron formulations differ by iron core size, carbohydrate shell identity/density, maximum dose, and cost. Some iron formulations have a higher chance of reactions than others. It is important to talk to your doctor about the type and amount of iron that is indicated for you.

These new guidelines give much needed clarity about the thresholds at which to treat iron deficiency. With how prevalent this condition is, the hope is that we can improve quality of life and reduce symptoms across the board. Doctors across all specialties should be able to at least screen for iron deficiency and hopefully the proper interventions will take place before someone becomes quite symptomatic from it.

Some content in this article was generated using artificial intelligence to illustrate and simplify explanation of scientific concepts. Images may not perfectly represent experimental workflows or scale. They are included to aid understanding rather than serve as primary scientific references.

Learn more about POTS here.

On instagram, you can follow Taylor @thehypermobilechiro and me @drpoorvidesai

So is it ever appropriate to use the words “cure” and “remission,” or is there better terminology? First, it is important to recognize that these terms are often used in the world of oncology, but they mean something very different when talking about non-cancerous, chronic conditions.

Disease Improvement Terms in Oncology

In oncology, “remission” describes a measurable reduction or disappearance of detectable tumor/malignant burden. We use standard response criteria which differ by tumor type (like RECIST 1.1 for solid tumors or Lugano criteria for lymphoma). Remission does not necessarily mean absence of disease. With advanced technologies we have even been able to detect minimal residual disease (MRD) which is low-level disease within a morphologic complete remission (CR).

• Complete remission/response (CR) means disappearance of all detectable disease.

• Partial remission/response (PR) means significant but incomplete tumor reduction.

“Cure”, by contrast, has no single agreed upon definition and can be approached in the ways listed below:

• Sterilizing cure — complete eradication of every malignant cell. This is an ideal that is inferred, never directly demonstrated, even in highly curable diseases like Acute Promyelocytic Leukemia or pediatric Acute Lymphoblastic Leukemia.

• Functional cure — residual disease or clonal abnormalities may persist but have no clinical relevance; no meaningful relapse, no need for ongoing intensive therapy, and survival approximating the general population. CML on/off tyrosine kinase inhibitors with sustained treatment-free remission is the prototype.

• Operational cure — a population-level statistical construct: when survival curves plateau with long follow-up and the hazard of relapse becomes negligible, a proportion of patients are considered cured in practical terms even if residual disease persists in some. In Hodgkin lymphoma and Diffuse Large B Cell Lymphoma, continuous CR beyond ~5 years is equated with cure.

Because “cure” has no single definition and it is a very final word, most oncologists prefer the term “complete remission” or “no evidence of disease.” We just know that there is no guarantee of freedom from relapse, even if the odds are very low.

Disease Improvement Terms in Chronic Inflammatory Illness

In chronic inflammatory conditions like rheumatoid arthritis (RA) or inflammatory bowel disease (IBD), “remission” describes suppression of disease activity to a state of minimal or absent clinical signs and symptoms—typically an ongoing, treatment-maintained state rather than eradication of disease.

The prototype of chronic inflammatory illness remission is rheumatoid arthritis (RA), which has two accepted definitions (Boolean-based or index-based) that include improvements in symptoms and inflammatory markers. “Remission” is symptom/activity-based (minimal or no symptoms as opposed to low or high disease activity states), and not anatomic or burden of disease-focused like in oncology. It is typically sustained by ongoing therapy like disease-modifying antirheumatic drugs (DMARDs), as tapering or stopping will frequently trigger flares. So a “sustained remission” in RA is frequently stated when there is ≥6 months of minimal/no symptoms and it is a prerequisite for considering treatment de-escalation.

The term “cure” is not used in these chronic inflammatory conditions. It is mainly a research aspiration rather than an accepted clinical outcome. The standard clinical language is “remission”—with sustained drug-free remission representing the most ambitious and realistic target.

Disease improvement terms in hEDS/HSD and related conditions

In both cancer and recognized chronic inflammatory conditions, the term “remission” is a formally standardized, criteria-based endpoint. Unfortunately, this is not the case for hypermobile EDS and related conditions:

Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobile Spectrum Disorders (HSD)

hEDS and HSD are the most common symptomatic joint hypermobility conditions, both diagnosed clinically using the 2017 International Classification criteria—HSD being the designation for patients with symptomatic joint hypermobility who do not meet the full criteria for hEDS. Neither has a known genetic mutation or a confirmatory laboratory test, and neither has a disease-modifying therapy. Management for both is aimed at symptom control, joint protection, and patient education. Although the 2017 criteria were intended to separate the two, they share the same extra-articular comorbidities (chronic pain, fatigue, dysautonomia, functional GI disorders, MCAS-type symptoms) and a similar long-term course and treatment response, which has led many experts to regard them as a single clinical spectrum rather than distinct diseases.

When the terms "remission" or "cure" are applied to hEDS or HSD, most who use them are trying to convey improvement in symptom control, functional improvement, and (variably) spontaneous or treatment-associated resolution of a defined diagnostic feature. So let's get into why that terminology should be challenged:

• There is no remission concept in hEDS and most of its common comorbidities. It is currently classified as an incurable chronic disorder managed by symptom control. This doesn’t mean that it does NOT have an inflammatory component, but because there is no measurable disease “activity” or “burden” to suppress or clear, the frameworks used in oncology (tumor burden) and RA or IBD (composite activity indices) do not map onto it.

• It is genetic and lifelong. hEDS is inherited in an autosomal dominant pattern, and the Nature Reviews Disease Primers group states plainly that no specific medical or genetic therapies exist for any type of EDS.

• The connective tissue trait does not go away. Even as symptoms wax and wane, the underlying collagen/connective-tissue predisposition remains. This is why the operative clinical goals are explicitly framed as managing symptoms, preventing joint injury, and patient education—not achieving disease-free status.

• The natural history is variable, not a “resolution.” Some features genuinely attenuate with age—Beighton scores tend to decline (often turning “negative,” <5) around the fourth decade, so joint laxity can lessen over time. A proposed three-phase model (hypermobility → pain → stiffness) describes typical evolution, though not every patient passes through all phases and transition rates vary widely. This reflects the evolving natural history rather than cure, and pain and fatigue frequently persist or generalize even as measured hypermobility falls.

Learn more about hEDS and HSD here.

Postural Orthostatic Tachycardia Syndrome (POTS)

POTS has the closest to a “remission” concept of all comorbidities, defined by loss of the diagnostic HR criterion. POTS has explicit diagnostic criteria (sustained ≥30 bpm HR rise—≥40 bpm in adolescents—on standing/tilt, without orthostatic hypotension, plus chronic symptoms for ≥3 months). “Remission” is used to mean a patient no longer meeting these criteria. But is important to note that non-orthostatic comorbid symptoms (fatigue, brain fog, GI symptoms, pain, anxiety) frequently persist even after the orthostatic tachycardia normalizes—so “remission” of the HR criterion does not equal resolution of the illness.

Learn more about POTS here.

Mast Cell Activation Syndrome (MCAS)

MCAS also has no remission criteria. The goal is symptom control and reduced anaphylaxis risk. The AAAAI defines MCAS by recurrent episodic systemic mast-cell activation typically affecting ≥2 organ systems, an event-related rise in serum tryptase above the patient’s baseline, and symptomatic response to mast-cell–directed therapy. There is no established remission definition, and no specific prognostic studies exist.

• Treatment is titrated to the individual’s mast cell mediator profile

• Therapy is generally long-term/maintenance; the practical goal is optimal quality of life with low risk of anaphylaxis rather than a defined remission state.

• Clonal MCAS carries a risk of progression to (usually indolent) systemic mastocytosis, so “control” also implies surveillance rather than cure.

Learn more about mast cells here.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

ME/CFS has no consensus definition of recovery or remission. These terms are used, but the definitions are inconsistent and contested.

• Using remission to mean the same thing as complete recovery is imprecise. Expert physicians conceptualize recovery as complete symptom remission plus return to premorbid functioning (age-adjusted), distinguished from significant improvement (substantial symptom reduction with functional gains but ongoing need to cope or be treated).

• A systematic review found nearly every study defined recovery differently (premorbid functioning, fatigue and function, fatigue alone, function alone, or brief global assessment), with recovery estimates ranging from 0–66% in intervention studies and 2.6–62% in naturalistic ones. The authors recommend the more precise label “clinically significant improvement” over “recovery.”

• Some argue definitions should rest on objective measures (e.g., repeat cardiopulmonary exercise testing capturing post-exertional malaise) rather than subjective fatigue scores.

• Population data illustrate the ambiguity: ~21% of ever-diagnosed U.S. adults report “past” ME/CFS (symptomatic remission), yet 40–50% of that group still report symptoms and function similar to current ME/CFS, and only ~25% have substantially better function—underscoring that self-reported remission often does not mean restored health.

Learn more about ME/CFS and PEM here.

So how should we explain symptomatic improvement in hypermobility and related conditions?

In hEDS/HSD, the underlying condition persists even when the clinical picture substantially improves. While there are patterns of comorbid conditions, what affects one individual with it will not always affect another. Focusing on specific comorbidities is more descriptive, such as with the following examples:

• “no longer meets POTS criteria”

• “anaphylaxis-free on mast-cell therapy”

• “clinically significant improvement in ME/CFS”

  • Reserve “recovery” only when both full symptom resolution and return to premorbid function are documented, ideally with patient-perceived recovery and normalization of both fatigue and function.

  • If describing the symptom dimension specifically (e.g., symptoms have resolved but function is not fully assessed or not fully restored), “symptomatic remission” is the precise term—and should be stated as such rather than implying full recovery.

As clinical criteria are refined for these conditions and more biomarkers emerge, the way we assess improvement may change. For now, rather than stating “remission” or “cure” of a single global state, it is more appropriate to describe improvement of specific symptoms and comorbidities.

Some content in this article was generated using artificial intelligence to illustrate and simplify explanation of scientific concepts. Images may not perfectly represent experimental workflows or scale. They are included to aid understanding rather than serve as primary scientific references.

References:

1. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12(6):e41-e63. doi:10.1016/j.hrthm.2015.03.029

2. Weiler C, Austen K, Akin C. AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management. Journal of Allergy and Clinical Immunology, 2019; 144, 883-896

3. Devendorf AR, Jackson CT, Sunnquist M, A Jason L. Defining and measuring recovery from myalgic encephalomyelitis and chronic fatigue syndrome: the physician perspective. Disabil Rehabil. 2019;41(2):158-165. doi:10.1080/09638288.2017.1383518

4. Studenic P, Aletaha D, de Wit M, et al. American College of Rheumatology/EULAR Remission Criteria for Rheumatoid Arthritis: 2022 Revision. Arthritis Rheumatol. 2023;75(1):15-22. doi:10.1002/art.42347

5. Scheper MC, Nicholson LL, Adams RD, Tofts L, Pacey V. The natural history of children with joint hypermobility syndrome and Ehlers-Danlos hypermobility type: a longitudinal cohort study. Rheumatology (Oxford). 2017;56(12):2073-2083. doi:10.1093/rheumatology/kex148

6. Yew KS, Kamps-Schmitt KA, Borge R. Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders. Am Fam Physician. 2021;103(8):481-492.

Post-exertional malaise (PEM) involves exacerbation of multiple symptoms beyond simple fatigue, including cognitive difficulties (brain fog), sleep disturbances, muscle pain, headaches, and flu-like symptoms. It can occur immediately after activity or can be delayed, and reflects a malfunctioning energy system with poor recovery. PEM is considered the hallmark and most important distinguishing symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

According to the American Academy of Family Physicians, PEM can be provoked not only by physical exertion but also by emotional, cognitive, and sensory challenges. The symptom exacerbation is disproportionate to the level of activity and is not substantially alleviated by rest. Patients with ME/CFS many times refer to these post-exertional episodes as “crashes.” There are 5 dimensions to PEM:

The 2015 National Academy of Medicine diagnostic criteria for ME/CFS require PEM as a mandatory criterion, along with substantial reduction in function lasting more than 6 months and unrefreshing sleep. Unlike the secondary fatigue associated with most chronic diseases that improves with exercise, ME/CFS patients experience prolonged worsening with even small increases in previously tolerated activities. This means that patients with ME/CFS need to be especially careful about exercise and exertion, as this can worsen the severity and duration of their symptoms.

#MEPedia is an advocacy/community resource which outlines four distinct characteristics of PEM with ME/CFS:

• Timing: A time lapse showing that PEM often has a delayed onset, hours or sometimes even days after the original trigger.

• Type of Symptoms: listed below

• Triggers: PEM is elicited after cognitive effort, physical exertion, or emotions

• Loss of Functional Capacity: decline seen on the second day of a 2 day cardiopulmonary exercise test (CPET)

ME/CFS Diagnosis

According to ME Action common symptoms of ME/CFS include:

• Orthostatic intolerance (symptoms that develop upon standing and are relieved by sitting or lying down)

• Unrefreshing sleep

• Pain in the muscles and joints

• Headaches of a new type, pattern, or severity

• Cognitive symptoms such as confusion, difficulty retrieving words, poor working memory, spatial instability, and disorientation

• Sensitivity to light, sound or vibration, taste, odor or touch

• Gastrointestinal symptoms such as nausea or abdominal pain

• Muscle fatiguability, weakness and fasciculation; poor coordination and ataxia

• Autonomic and endocrine symptoms such as poor temperature regulation, cold or heat intolerance

• Immune symptoms such as tender lymph nodes, recurrent sore throats, fevers, or flu-like symptoms, and new food or chemical sensitivities

The onset and duration of PEM vary considerably among individuals. In one study of ME/CFS patients, 11% reported a consistent delay of at least 24 hours before symptom onset, while 84% experienced PEM lasting 24 hours or more. Following controlled cardiopulmonary exercise testing, most patients (17 out of 18) reported symptoms starting within 24 hours and peaking within 72 hours. However, in daily life, patients report that PEM can last from a few days to several months.

What causes PEM?

The pathophysiology of PEM is thought to involve a self-reinforcing cycle of mitochondrial dysfunction, immune activation, and neuroinflammation — an "energy exhaustion–inflammation amplification" loop.

Exercise testing in patients with ME/CFS has revealed markers that are normal in a resting state but abnormal after exertion. Neurologic, immunologic, and oxidative stress patterns appear to be affected in the pathways leading to PEM.

A 2012 study showed that the presence of stress factors in the history of ME patients is associated with severe oxidative stress and the suppression of protective heat shock proteins HSP27 and HSP70 responses to exercise. Cellular respiration relies on redox (reduction-oxidation) reactions and this study suggests that this might be impaired in ME/CFS patients.

PEM can be demonstrated by a 2-day cardiopulmonary exercise test (CPET) procedure. VO2 max (maximal oxygen consumption) is the maximum rate at which the body can uptake and utilize oxygen during incremental exercise, expressed in mL/kg/min or L/min. It is considered the gold standard measure of cardiorespiratory fitness. On the second day of CPET, ME/CFS patients display a significant drop in VO2 max and/or anaerobic threshold that is not typically seen in healthy controls. These objective measures track strongly with the presence, severity, and duration of PEM.

The DecodeME Study identified 22,411 reproducible disease signatures mapping to 2,311 genes. Participants with the highest signature counts had 1.64 times greater odds of ME compared to those with the lowest counts, confirming a genetic basis for disease susceptibility. There was also substantial overlap in signatures found in long COVID. Overall, DecodeME shows that ME/CFS is partly attributed to 259 candidate genes related to neurological dysregulation, inflammation, cellular stress responses, and calcium signaling.

CrunchME is a data-informed advocacy platform to accelerate research & progress on ME/CFS, Long COVID & other infection-associated chronic illnesses. In collaboration with they recently published 6 areas of physiologic abnormality in ME/CFS.

1. Metabolic Dysfunction

2. Immune Activation and Exhaustion

3. Autonomic Dysfunction

4. Vascular and Cardiac System

5. Gut Microbiome

6. Genetic Risk Factors

How do PEM and ME/CFS relate to hEDS/HSD?

Fatigue affects approximately 82% of patients with hEDS, according to a cross-sectional survey study that characterized the lived experience and symptom burden of adults with hEDS. There are several reasons for fatigue in hEDS including chronic pain, orthostatic intolerance, exercise intolerance, neuromuscular involvement, sleep disorders, psychological distress, nutritional deficiencies, among others. However ME/CFS requires the above diagnostic criteria to be met, and these tend to overlap significantly with those experienced by patients with hEDS.

Another cross-sectional survey study by Collins et. al examined autonomic symptom burden, comorbidities, and quality of life in 84 women with physician-diagnosed hypermobility spectrum disorders (HSD) or hypermobile Ehlers-Danlos syndrome (h-EDS) using validated questionnaires including COMPASS-31, SF-36, and BDI-II. The study concluded that women with hEDS/HSD experience severe autonomic dysfunction, chronic pain, multiple chronic comorbid conditions, and markedly reduced quality of life. Questionnaire scores were significantly higher than scores reported in patients with multiple sclerosis, diabetic neuropathy, scleroderma, and psoriatic arthritis.

Comorbidities that were highly prevalent:

• 58.3% had physician-diagnosed POTS

• 54.8% had migraines

• 32.1% had mast cell activation syndrome (MCAS) - this is likely an underestimation

• 26.2% had ME/CFS

• 98.8% reported chronic pain

• 25% had the clinical triad of HSD/hEDS, POTS, and MCAS

A study using You + ME registry data found that 15.5% of ME/CFS patients had joint hypermobility, and among those with both ME/CFS and joint hypermobility, there was a higher likelihood of reporting hEDS. Another study looking at fibromyalgia, ME/CFS, and hypermobility found that 81% met Brighton criteria for hypermobility syndrome and 18% met 2017 hEDS criteria. This suggests substantial overlap between the conditions.

How do PEM, ME/CFS, and Hypermobility relate to Long COVID?

PEM has emerged as a key symptom in Long COVID/Post-Acute Sequelae of COVID (PASC). According to a 2024 narrative review in Frontiers in Neurology, hypermobility has been detected in 30-57% of patients with ME/CFS, and joint hypermobility is increasingly recognized in Long COVID patients. Among Long COVID patients at Mayo Clinic, 27% screened positive for generalized joint hypermobility compared to 10% of controls, and 58% met criteria for ME/CFS. The authors propose that mast cell activation and persistent inflammation may link these conditions through connective tissue damage. Based on their synthesis of the literature, they recommend screening for hypermobility in long COVID patients and suggest symptom-focused pharmacological treatments along with paced exercise, yoga, and meditation.

Due to the increasing prevalence of ME/CFS with long COVID, more research is required to understand the current thinking about disease mechanisms and clinical relationships. Treatment options are limited at this time but will hopefully expand with robust clinical trials as more pathways of understanding are uncovered.

Resources and community support for ME/CFS:

MEAction

#MEPedia

BHC ME/CFS Crash Survival Guide

Millions Missing

CDC Patient Toolkit ME/CFS

CrunchME

Some content in this article was generated using artificial intelligence to illustrate and simplify explanation of scientific concepts. Images may not perfectly represent experimental workflows or scale. They are included to aid understanding rather than serve as primary scientific references.

You may have heard the term “MCAS” or Mast Cell Activation Syndrome, and wondered what exactly is a mast cell?

According to the National Cancer Institute:

“Mast Cell- A type of white blood cell that is found in connective tissues all through the body, especially under the skin, near blood vessels and lymph vessels, in nerves, and in the lungs and intestines. Mast cells play an important role in how the immune system responds to certain bacteria and parasites and they help control other types of immune responses. They contain chemicals such as histamine, heparin, cytokines, and growth factors. They release these chemicals during allergic reactions and certain immune responses. These chemicals have many effects, including the widening of blood vessels and angiogenesis. During an allergic response, they can cause flushing (a hot, red face) and itching. In large amounts, they can also cause abdominal cramps, muscle pain, nausea, vomiting, diarrhea, low blood pressure, and shock. Mast cells are part of the body’s immune system.”

I am a hematologist/oncologist, which means that I am a specialist of all things cells, blood, and cancer. In my field, mast cell disorders are generally regarded when they develop a mutation and turn into a cancerous process. Management of benign, noncancerous mast cell conditions is usually deferred to the field of allergy/immunology, but they still remain poorly understood and the criteria for diagnosing mast cell activation is contended. Mast cells were historically thought to be elusive. In fact, many times mast cells are even omitted from a typical diagram showing stem cell differentiation.

Stem Cell Differentiation (a complete version) looks like this:

Stem cell differentiation. Image from Cell Signal Technology .

Why are Mast Cells Overlooked?

This may be because mast cells can be incredibly difficult to detect. They do not normally circulate in your blood, so they do not show up on a routine complete blood count (CBC) with differential. Only in certain cancerous conditions, most notably in advanced systemic mastocytosis, circulating mast cells can be detected in the blood and their presence is associated with a poor prognosis and aggressive disease. This detection is a biomarker of disseminated disease which is not seen in healthy individuals or in most allergic conditions. But just because they are hard to detect does not mean that they aren’t real or causing symptoms.

Where are Mast Cells Found?

After leaving the bone marrow, mast cells migrate out into peripheral tissues where they reside. They are generally present at interfaces between the body and the external environment, so you can think of them as a type of front line army against any external threat trying to come in to the body. As per the above NCI classification of mast cells they are “found in connective tissues all through the body, especially under the skin, near blood vessels and lymph vessels, in nerves, and in the lungs and intestines”

What is the Purpose of A Mast Cell?

The primary role of a mast cell is to be the first line of defense for the immune system.

They have cytoplasmic granules containing preformed mediators, including histamine, heparin, and proteases (e.g., tryptase, chymase).

Mast cells can be “triggered” by all kinds of input signals. They have a wide array of receptors so can be activated by immunoglobulins, complement, cytokines, neuropeptides, and pathogen-associated molecular patterns. They will then release their preformed mediators and the result can be itching, hives, swelling, inflammation, breathing difficulties, gastrointestinal symptoms, among many others. The specific effect depends on the mediators released and the target organs involved.

Adapted from: Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. July 8, 2015.

Mast Cell Markers

Overall it is very difficult to test for mast cells because they are quite elusive. They release their granule contents which don’t stick around in the blood long to be detected easily.

While both mast cells and basophils express FcεRIA, the combined expression of FcεRIA and CD117 (also known as c-kit) is unique to mast cells. Mast cells can also be identified by their high expression of serum tryptase, a granule protein. Serum tryptase is the most validated and widely used blood biomarker for mast cell activation, but other proposed mediators (urinary prostaglandins, histamine metabolites) have significant preanalytical variability that limits their clinical utility.

AAAAI endorses a “strict” consensus-1 criteria for MCAS where biomarkers must be present during an active flare. This is the most validated by professional societies and requires three elements:

1. typical clinical symptoms

2. a transient increase in a validated mast cell mediator (most commonly serum tryptase rising ≥20% + 2 ng/mL above baseline)

3. response to mast-cell directed therapy

Consensus-1 is being challenged by another “loose” consensus-2 criteria which focus less on the presence of elusive biomarkers and instead the constellation of clinical symptoms to diagnose the condition. AAAAI and other professional societies believe that use of these looser criteria may lead to overdiagnosis and overtreatment of MCAS, as many of the symptoms attributed to mast cell activation (flushing, GI distress, fatigue) are nonspecific and overlap with numerous other conditions. Both criteria maintain that there should be a response to mast-cell directed therapies.

Regardless, it is clear that biomarkers for MCAS are lacking and further research is needed to identify them better if we are to depend on them for diagnostic criteria.

Some content in this article was generated using artificial intelligence to illustrate and simplify explanation of scientific concepts. Images may not perfectly represent experimental workflows or scale. They are included to aid understanding rather than serve as primary scientific references.

The sturdy, heavy build of a Porsche makes you feel like the car is invincible. 21 inch tires make you feel like you are elevated and untouchable. The steady steering and smooth ride helped me feel less whiplash and like I was being swaddled. I chose my car because of these comfort and safety features. The 14-way power adjustable seats solidified my decision and I have never regretted it.

In many ways I knew that the name “Porsche” would carry weight. I just never knew how much. I quickly began to hear comments about my new car- just a few that were negative (apparently I am “spoiling the Porsche name by getting an SUV”) but mostly pretty encouraging and filled with awe, maybe even envy. Overall, a Porsche is mark of excellence. A status symbol, if you may.

People have certain expectations about a Porsche. The shiny exterior, engineering excellence, loud exhaust, maximum horsepower…overall the brand identity that states “this car can do things regular cars just can’t. This car can make you feel things regular cars just can’t.” And because it can, it should.”

On July 4, 2026, America’s 250th birthday, I was leaving one party to head to the next. I got into my Macan on that humid 95 degree day, heard the loud rev of the engine, blasted my AC and seat coolers, and went on my way. To be honest I get a bit scared about driving on major holidays. Too many drunk drivers. But the sun was still out and I only had a 15 minute drive. I turned on my Spotify music playlist on my surround sound system and felt the anxiety melt away. As I cruised down the interstate jamming out, I was jolted out of my bliss by a loud thud on the right side of my car. Something definitely just hit me. I was in the leftmost lane of a 5 lane highway and suddenly my perfect Titanic of a Macan let out a screech- (!)WARNING(!). Within seconds I saw my right front tire pressure indicator fall. First -6. Oh my, this sucks. I’ll have to get to the nearest tire shop and fill up the pressure. Then -18. Wait this is not looking good, I need to cross 4 lanes and get to the right shoulder. Now -24. Get your hazard lights on, Poorvi. GTFO of this interstate. Finally -38. Uh-oh. This tire is busted.

Because of POTS my nervous system is dysregulated at baseline and this kind of misadventure was sending blaring alarms through my body. Thank God for Triple A roadside assistance and friends who come to your rescue. With shaking hands I called both and within 10 minutes they had arrived. They assured me that there was no need to tow. The tire simply needed to be replaced by the spare in my trunk.

Another 20 minutes later and the magician of a technician had managed to replace my tire in the middle of a busy highway, complete with many a head shakes and bird flips to those who would not merge out of the right lane to give him space to work, otherwise he could have timed it at 10 minutes tops. When he let me know that everything was good to go he told me to remember “The 50-50 rule.” You can’t drive more than 50 miles per hour or more than 50 miles total on this spare tire. Additionally, the spare is a good 3 inches smaller than the other tires. A front tire is a steering tire. I would have to be really careful driving this thing home.

One sudden harm event and everything changed. Here was my Porsche, groomed for speed and agility, now unable to drive faster than 50 mph even on an interstate. As I merged back onto the highway I quickly realized how impatient most of the drivers were when I couldn’t keep up with their speed. Even with my hazards on, they tailed then sped past me, frustrated I wouldn’t just go faster. Especially in a Porsche. This is so embarrassing. An odd sense overcame me, being tempted to just hit the gas like I knew my precious car was made for. The optics were there- the car looked just fine. Why not just push past the limit and fit in with the other drivers to behave the way they wanted me to? For a split second they got to my inner thoughts. Maybe they just say 50mph to scare you. Maybe you’re good pushing the limit a little bit. Do what you need to do to fit in.

Then it hit me that this odd sense felt familiar. My life, like many with hypermobility, used to be a lot like speeding down the highway in a Porsche. I was agile and elevated. People saw my credentials and appearance as something to envy. “Homecoming court and then a doctor at 23? You really are beauty and brains!” were the kinds of things I got used to hearing. It wasn’t always the easiest to pull off, but I could just adjust and keep up my shiny appearance. Then my “triggering event” happened and I very suddenly could not adjust anymore- my body was just done. In other words, the Porsche steering tire of my life suddenly got hit and within minutes, deflated. It was then and only then when I realized how much of the accolades were more than just compliments and encouragement, they were an expectation. If I was going to “look fine” then I better act fine. I better be fine. Otherwise, how do I justify complaining while having all that beauty and brains privilege? How can I prove that until very recently I was able to climb to the top of every challenge, but now I can’t get out of bed for four days straight?

The tire replacement was like the emergency room- an acute care visit meant to patch up the life threatening problem so at least there was a temporary fix until the elusive “someone else” could figure out a long term solution. Services rushed to fix the flat tire, but I was on my own once that happened. I knew that my car couldn’t handle a higher speed with my spare tire, regardless of how it looked. People ignored my hazard lights so tailed me, flipped me off, and honked at me anyways. They saw me as driving slow in a Porsche (ew) and ruining their day (how dare I?). They didn’t see the handicapped spare tire meant to simply help me get from Point A to Point B. My car was now fighting for the most basic of transportation duties.

Now I had to carefully navigate the spare tire in ways I didn’t anticipate. The steering direction, precision handling load, and responsiveness were all tied to a tire I took for granted. It needed an even stronger grip and more control with merging lanes and taking turns. Braking felt more jolting than ever. All of these things I didn’t usually have think about I was now suddenly hypervigilant of. I knew that I had to think about every micro movement and not blow past this tire’s limits or I would be in even worse condition. This felt a lot like dysautonomia. The autonomic nervous system is one that takes care of body functions that you’re not supposed to have to think about. Things like breathing, digesting food, regulating your body temperature and your blood pressure. For a while now I have been living without the privilege of a functioning autonomic nervous system. Now I was living without the privilege of a functioning steering tire. This spare was slowing me down and making me face a rushed world that expected the opposite. I thought to myself, I am a spare tire.

My friends checked in on me and made sure I made it home in one piece. “I’ll follow you until I see you’ve taken the exit.” “Make sure you turn your hazards off when it’s safe.” Amidst the odd feelings of pressure by the speedy drivers around me, I realized how lucky I was to have the support of community that cared. Because just like when life hits you with the curveball of a flat tire, it can just as easily hit you with the curveball of an illness. In both of those moments you may get caught up in past appearances that served you and be tempted to keep them up. But that’s when you realize that the people who encourage you to endanger yourself for the sake of said appearances aren’t true support. What will get you through is your own self-acceptance and the village of people who love and care for you despite what you look like or produce for them. It’s not just the permission to rest and use adaptations, but the encouragement of it for your wellbeing. It’s making sure you know that whether you are a Porsche or a Honda, a regular tire or a spare tire, you’re pretty cool for just having the basic makeup of a car that is meant to do one thing- safely navigate you through this life.

Several years ago, NASA realized that astronauts who returned from long space flights were experiencing trouble standing, dizziness, tachycardia, and even fainting after returning to the gravitational pull of the Earth. Relatable? According to a paper by Goswami et al, the brain lacks a gravity-sensing region and instead relies on a network called graviception to interpret the effect of gravity. On Earth, gravity causes blood to pool in the legs which triggers compensatory responses to constrict blood vessels and preserve perfusion to the brain. In microgravity, blood is no longer pooled in the legs so fluids shift upwards, and this compensatory mechanism is not forced to work. With prolonged spaceflight astronauts develop accelerated muscle and bone loss, cardiovascular deconditioning, decreased maximal oxygen uptake (VO2 max), and loss of autonomic nervous system functioning. Think “if you don’t use it you lose it.” This all leads to orthostatic intolerance upon returning to the Earth, which means that astronauts need to retrain their bodies when they return from space.

In order to assess orthostatic intolerance in astronauts, NASA developed a test where they had them:

• First, lay supine to assess their baseline heart rate and blood pressure without the pull of gravity.

• Then, stand and lean slightly against a wall with their heels a few inches away for 10 minutes. This position ensures passive standing which reduces muscle intervention and therefore venous return of blood to the heart.

• Blood pressure and heart rate are taken at every minute to see how they changed with the orthostatic symptoms.

If this sounds familiar, this test is called the 10-minute NASA Lean Test and it is still used today to diagnose conditions with orthostatic intolerance like POTS, ME/CFS, and Long Covid.

Countermeasures

Exercising pre-flight significantly improved the cardiovascular fitness of astronauts but did not always lead to eliminating post-flight orthostatic intolerance. So in 2019, UT Southwestern conducted a study of 13 astronauts who were given countermeasures with in-flight individual exercises and fluid resuscitation as they returned to Earth. Cardiovascular data such as heart rate and variability in blood pressure was measured before flight, during flight, and on landing day. With the countermeasures after 6 months in space, none of the astronauts developed orthostatic intolerance during routine (for landing day) activities in the initial 24 hours after landing. These countermeasures include:

• structured exercise regimens

• nutritional optimization

• fluid management protocols

• limited pharmacologic interventions

Today, astronauts average about two hours of exercise per day while in space.

What can this teach us about POTS?

Prior to spaceflight, astronauts are healthy and have preserved compensatory mechanisms when blood pools in their legs. It is microgravity that stops forcing these compensatory mechanisms, and they become temporarily deconditioned. Astronauts will be able to take countermeasures like exercise, intravenous fluids, and vestibular retraining to fully adapt back to the Earth’s gravity. In comparison, patients with POTS have a faulty compensatory mechanism against gravity at baseline, right here on Earth.

Both, however, have “triggers” that set off or worsen their orthostatic intolerance. While the “trigger” for astronauts is microgravity, it is similar to the “triggers” that patients with POTS face, like infections or physical/emotional traumas which have compromised their body’s ability to adapt. The countermeasures taken help both astronauts and patients with POTS fight their orthostatic symptoms and the physiologic effects of gravity.

Many view prolonged spaceflight as a model for accelerated aging and as an analog to chronic illness and frailty. Studying the effects of gravity and microgravity on astronauts has left us with several insights:

• how bodies can fail to adapt to gravitational changes

• how important countermeasures such as neurologic rehab, individual cardiovascular exercise, and intravascular volume expansion are for people who struggle with orthostatic intolerance

• that targeted interventions can safeguard astronaut health and translate into novel therapies for those with chronic illness and older adults.

• an easy and effective way to measure orthostatic intolerance on Earth with the NASA Lean Test.

As we welcome back the astronauts of the historic Artemis II trip around the moon, we will see them struggle to adapt back to the effects of gravity on Earth. My takeaway is that we just cannot fully blame the orthostatic intolerance astronauts face as being from deconditioning, as we know that astronauts are some of the most well conditioned humans on the planet. Re-conditioning with individualized strength training regimens and volume expansion helps to prevent and treat the effects of microgravity, just like these same countermeasures help patients with POTS.

Some content in this article was generated using artificial intelligence to illustrate and simplify explanation of scientific concepts. Images may not perfectly represent experimental workflows or scale. They are included to aid understanding rather than serve as primary scientific references.

What is Connective Tissue?

Think of connective tissue as the “glue” that holds all the different parts of your body together. The purpose of connective tissue is to support organs and cells, transport nutrients and wastes, defend against pathogens, store fat, and repair damaged tissues.

When you are hypermobile, connective tissues are not as strong as they normally should be. There are several different types of connective tissue. EDS develops when there are one or more inherited mutations that lead to defects within the development and/or processing of connective tissue,2 and is generally known as a defect involving collagen fibrils. Because connective tissue is present throughout the body, from larger joints to smaller blood vessels, hypermobility has the potential to affect any and all organ systems.

Image created in https://BioRender.com

Image created in https://BioRender.com

Types of Connective Tissue

1. Connective Tissue Proper

   1. Loose (areolar) Connective Tissue → less dense and compact

      1. Holds organs, anatomic structures, and tissues in place.

      2. Large spaces between fibers

   2. Dense Connective Tissue → Higher density of fibers, more compact.

      1. Parallel fibers: all in one direction. Ex = Tendons and ligaments

      2. Irregular fibers: multidirectional. Ex = pericardium (heart lining)

      3. Elasatic: embedded elastin. Ex = blood vessel linings

   3. Histology: Three Fiber Types of Connective Tissue Proper

      1. Collagen

         1. The most abundant protein in your body (30%)

         2. non-elastic

         3. Packed and bundled, providing powerful resistance to pulling force

      2. Reticular

         1. Functional and structural unit to support tissues

         2. More loosely arranged

      3. Elastic

         1. Main protein = Elastin

         2. Elastic fibers have recoil ability, and are generally a loose network

         3. Found in distensible and contractable organs (blood vessels, lungs, bladder)

2. Specialized Connective Tissue

   1. Adipose (fat), Cartilage, Bone, Blood, and Lymphatic Tissues

Types of Collagen

Classifying EDS According to Collagen Type or Processing Protein Affected

Hypermobile EDS (hEDS) and Hypermobile Spectrum Disorders (HSD)

In 2022, a study from Italy that used biopsies of dermal fibroblasts (structural skin cells) of patients with hEDS and HSD showed that both cell types had a disorganized structure with generalized extracellular matrix disarray, myofibroblast differentiation, and dysregulated gene expression. This showed that the underlying structural patterns are the same in both hEDS and HSD, and that they are likely the same condition on a spectrum of varying severity.3

Image from EDS Society

Fascia

Fascia is a three-dimensional network of connective tissue that surrounds bones, muscles, nerves, and blood vessels. It is composed of specialized cells, collagen and elastin fibers that provide mechanical strength, and extracellular matrix (ground substance) which provides plasticity and elasticity. The words “fascia” and “connective tissue” are many times used interchangeably.

Chronic pain can develop when there is an abnormality in fascia. Fibroblasts that make up collagen are dysfunctional and lead to to increased tissue stiffness4 Fascia is rich with blood vessels, lymphatics, and hormonal and neurotransmitter receptors5 It was once thought to be an inert (passive) material. However it is now recognized to house an estimated 250 million nerve endings, which is 25% more nerve endings than skin and 1000% more than muscle, so fascia could be considered our richest sensory organ.6 As a key regulator of the body’s sensory input, fascia plays a role in neurovascular, hormonal, endocrine, musculoskeletal, inflammatory, and hypermobility-related conditions.

It is very difficult to strengthen connective tissue when there is a defective structural issue, but lifestyle modifications that reduce energy expenditure, minimize damage, strengthen muscle, and retrain the nervous system can help keep connective tissues intact.

Our nervous system consists of central and peripheral branches. The Central Nervous System (CNS) refers to the brain and spinal cord while the Peripheral Nervous System (PNS) encompasses all nerves outside of the CNS. The Autonomic Nervous System (ANS) is a part of the PNS. It is not truly autonomic, meaning it does not function completely separately from the CNS. But it is automatic, meaning it should be an unconscious and involuntary regulator, coordinating the following functions1 :

• Controlling blood flow to the brain and organs while at rest and exercising

• Regulating body temperature

• Digesting food for energy production and fuel delivery

• Waste management (urination and defecation)

• sympathetic activation in dangerous situations

The Autonomic Nervous System has three components:

• Sympathetic Nervous System (SNS): fight and flight responses

• Parasympathetic Nervous System (PNS): rest and digest responses

• Enteric Nervous System (ENS): food movement through the gastrointestinal tract, gastric acid secretion, local blood flow, and hormone release within the gut

What is Dysautonomia?

Dysautonomia is an umbrella term to describe malfunction of the autonomic nervous system2. There are many different types of dysautonomias. The most common type in patients with hypermobility is orthostatic intolerance, or postural orthostatic tachycardia syndrome (POTS). In fact, it is estimated that about 70% of patients with hypermobile EDS have POTS3, and about 50% of all patients with POTS have hypermobility4. This is when patients feel the best laying down, and can start feeling dizzy or lightheaded, even to the point of syncope (passing out) when standing, or sometimes even upon just tilting the head upwards or sitting upright.

Many patients with POTS can point to a “triggering event” after which they noticed their symptoms did not improve. These triggering events can be an infection like COVID-19, physical trauma like a motor vehicle accident, or an emotional trauma/perceived catastrophic event. The majority of patients with POTS are young females who were active and healthy prior to this triggering event, at the peak of their education and beginning of their working lives. This event is thought to be a loss of vagal tone, which exists to keep the nervous system in a calm state (parasympathetic). The result of this loss can be inflammation, immune dysfunction, fatigue, and pain.

Symptoms of Orthostatic Intolerance. Image from The Dysautonomia Project.5

What is Postural Orthostatic Tachycardia Syndrome?

The exact definition of POTS is the following:

• For Ages 12-19: Heart rate increase of >40 beats per minute (bpm) within 10 minutes of head up tilt

• For Ages >19: Heart rate increase of >30 bpm within 10 minutes of head up tilt or stand or HR >120 bpm

• Absence of orthostatic hypotension which is a sustained blood pressure decrease of >20/10 within 3 minutes of head up tilt/standing

If the above criteria are not met but patients still have symptoms, they are considered to have “chronic orthostatic intolerance” or “postural symptoms without tachycardia,” which are essentially treated the same way as POTS.

What explains POTS?

POTS is explained by the physiology of the baroreceptor reflex6, which is when pressure changes in the carotid arteries (vessels in the neck that oxygenate the brain, face and neck) and aorta (largest blood vessel that oxygenates blood from the heart to the rest of the body) stimulate changes in blood pressure and heart rate to regulate with gravity. In EDS, where blood vessels and the the heart do not have enough “squeezing power,” the brain does not get enough blood flow upon standing, and the carotid arteries and aorta do not fill to the proper amount. The end result is that the reflex sends out sympathetic “fight or flight” responses to increase the heart rate to make up for the lack of blood flow to the brain.

Physiological mechanisms involved in regulating blood flow with orthostasis (left) and order of activation of physiologicalchanges that occur with standing (right). Image obtained from Khan et. al, “Cerebral Blood Flow in Orthostatic Intolerance” JAHA, 2025 with permission by publisher John Wiley and Sons.

Physiology of POTS showing reduced blood volume and increased heart rate upon standing. Image created in BioRender, adapted from Lurie Children’s Hospital of Chicago.

There are different subtypes of POTS. Hypovolemic, hyperadrenergic, and neuropathic subtypes are seen most commonly in patients with hypermobility, and the phenotypes (observable characteristics) of these three often overlap. Other subtypes of POTS include autoimmune, deconditioning, or secondary to another disease process like chemotherapy, radiation to the neck, injury to the spinal cord or neck, diabetes, or a drug effect.

Phenotype based classification and management of POTS7. Image adapted from Gazal, et al. 2025.

Hypovolemic POTS

• minimal to no change in blood pressure but elevated heart rate upon standing

• The majority of POTS patients have hypovolemia (low blood volume) despite adequate hydration. Standard blood and urine tests may not detect this hypovolemia as patients may be deficient in plasma and red blood cells8

• estimated plasma volume deficit of 13%9

• Likely due to abnormalities in the renin-angiotensin-aldosterone system which regulates sodium retention and blood volume.

Hyperadrenergic POTS

• increase in blood pressure, heart rate upon standing

• extremely high levels of upright plasma norepinephrine (>1000 pg/mL and occasionally >2000 pg/mL), which is a marker of excessive sympathetic discharge.

• most commonly secondary to a partial dysautonomia or hypovolemia.

• hypovolemic POTS may “switch” into a hyperadrenergic subtype due to longstanding, excessive sympathetic overdrive that compensates for their low blood volume.

• some patients may have a mutation causing loss of function in the norepinephrine transporter, leading to the inability of the body to clear norepinephrine and therefore levels become too high.

Neuropathic POTS

• no change in blood pressure but dramatic increase in heart rate upon standing

• A form of dysautonomia with less norepinephrine release, and therefore less sympathetic activation, in lower extremities10

While these three subtypes seem to have distinct mechanisms of action, they share overlapping symptoms and are not mutually exclusive from each other. Many patients may have features consistent with more than one subtype leading to overlapping subsets as visualized here.11

• Joint Hypermobility

  • Diagnosed based on the Beighton Score and 5-part hypermobility questionnaire2

  • Having a greater range of motion than joints in general

• Hypermobile Ehlers-Danlos Syndrome (hEDS)

  Diagnosed based on the 2017 International Criteria for Hypermobile Ehlers-Danlos Syndrome, Published by the EDS Society3

  • Criterion 1: presence of generalized joint hypermobility

  • Criterion 2: manifestation of a connective tissue disorder, family history, and musculoskeletal complications

  • Criterion 3: The absence of another hereditary disorder of connective tissue or other cause for relevant signs or symptoms found.

• Hypermobile Spectrum Disorders (HSDs)

  • Diagnosed “in between” Joint Hypermobility and hEDS

  • Same musculoskeletal concerns seen in hEDS but with the absence of sufficient additional features to make a diagnosis of hEDS or other hereditary disorder of connective tissue.

  • A key feature is the distribution of hypermobility: HSD can be generalized, local/regional, or peripheral (small joints) while hEDS must be generalized.

  • There are four currently described subtypes of HSDs4:

    • Generalized (joint) HSD (G-HSD): GJH objectively assessed utilizing a clinical score such as the Beighton score plus one or more secondary musculoskeletal manifestations.

    • Peripheral (joint) HSD (P-HSD): JH limited to hands and feet plus one or more secondary musculoskeletal manifestations.

    • Localized (joint) HSD (L-HSD): JH at single joints or group of joints plus one or more secondary musculoskeletal manifestations regionally related to the hypermobile joint(s).

    • Historical (joint) HSD (H-HSD): self-reported (historical) GJH by the 5PQ with a negative BS plus one or more secondary musculoskeletal manifestations.

Hypermobility can have primary or secondary causes. Genetic causes such as Ehlers-Danlos Syndrome are inherited connective tissue disorders and a primary cause for hypermobility. Hypermobility can also be secondary to inflammation or other trauma that weakens and destabilizes joints. Many children and adolescents can have hypermobility which resolves with age. There are also hormonal effects of hypermobility, such as in pregnancy when levels of progesterone and relaxin increase with the intent to loosen joints and prepare for childbirth.5

It is important to have an individualized approach to your care for hypermobility. Working with your doctor to identify the underlying cause of your hypermobility will help to find treatment solutions that work for you.

The EDS “Triad”

1. Hypermobility

2. Postural Orthostatic Tachyardia Syndrome

3. Mast Cell Activation Syndrome

Image adapted from Kucharik, Chang: Clinical Reviews in Allergy &amp; Immunology, vol. 58, no. 3, 2 July 2019, pp. 273–297, https://doi.org/10.1007/s12016-019-08755-8.

Hypermobility refers to a condition of having an unusually or abnormally great range of movement. Currently it is diagnosed using the Beighton Score, though there are several limitations to utilizing just this for diagnosis. Hypermobility exists on a spectrum, and not everyone with hypermobility will have hypermobile EDS. Hypermobile EDS is diagnosed using the 2017 hEDS Diagnostic Criteria.

Postural Orthostatic Tachycardia Syndrome, or POTS, is a term to describe a group of disorders that feature orthostatic intolerance, which is when a person becomes symptomatic when standing up and relieved by lying down.2 POTS is a type of dysautonomia, a disorder of the autonomic nervous system (ANS). When the ANS is properly functioning it will maintain balance between heart rate and blood pressure during positional changes. Blood flow does not reach the heart or brain as it should when positioned upright, and patients can feel dizzy, lightheaded, and even pass out. Patients with POTS will have a fast heartbeat, or tachycardia, which improves when lying down.

Mast Cell Activation Syndrome, or MCAS, is a condition in which a person experiences repeated episodes of allergic symptoms such as hives, swelling, low blood pressure, difficulty breathing, and severe diarrhea3. Mast cells are immune cells that reside in connective tissues. When they are activated, they release different mediators like histamine, tryptase, heparin, and proteases that can result in allergic type symptoms. MCAS is the dysregulated activation of these cells. It is still poorly understood as both mast cells and their mediators are difficult to measure, however several patients with the triad respond favorably to antihistamines and other medications that suppress the activation of mast cells.

A review of the triad by Dr. Leonard Weinstock in 2024 showed that complex patients with a “very positive review of symptoms” requires consideration that the Triad syndromes will provide a unifying diagnosis.4 While there is no “cure” for EDS, there are strategies to mitigate the triad with education, lifestyle changes, and if needed, pharmacologic treatments. It is important to take all symptoms into context as the saying goes “if you can’t connect the issues, think connective tissues.”