The Provider Primer Series: Mediator testing

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[i].
  • Objective evidence of mast cell mediator release is required for diagnosis of MCAS (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in MCAS testing recommendations (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[v]; plasma heparin[ix]; serum chromogranin A[ix]; and leukotriene E4[ix].


  • Tryptase is extremely specific for mast cell activation in the absence of hematologic malignancy or advanced kidney disease. Of note, rheumatoid factor can cause false elevation of tryptase[ix].
  • Serum tryptase levels peak 15-120 minutes after release with an estimated half-life of two hours[vi].
  • Per key opinion leaders, tryptase levels should be drawn 15 minutes to 4 hours after onset of anaphylaxis or activation event (Castells 2013[ii]), (Akin 2010[iii]), (Valent 2012)[iv]). Phadia, the manufacturer of the ImmunoCap® test to quantify tryptase, recommends that blood be drawn 15 minutes to 3 hours after event onset[vii].
  • Serum tryptase >11.4 ng/mL is elevated[i]. In addition to measuring tryptase level during the event, another sample should be drawn 24-48 hours after the event, and a third sample drawn two weeks later. This allows comparison of event tryptase level to baseline[vi].
  • An increase in serum tryptase level during an event by 20% + 2 ng/mL above patient baseline is often accepted as evidence of mast cell activation[v],[i].
  • Absent elevation of tryptase level from baseline during an event does not exclude mast cell activation[viii].
  • Sensitivity for serum tryptase assay in MCAS patients was assessed as 10% in a 2014 paper[ix].
  • A recent retrospective study of almost 200 patients found serum was elevated in 8.8% of MCAS patients[x].
  • Baseline tryptase >20.0 ng/mL is a minor criterion for diagnosis of systemic mastocytosis. 77-85% of SM patients have baseline tryptase >20.0 ng/mL[ix].

Histamine and degradation product n-methylhistamine

  • N-methylhistamine is the breakdown product of histamine.
  • Histamine is degraded quickly. Samples should be drawn within 15 minutes of episode onset[vii].
  • Serum histamine levels peak 5 minutes after release and return to baseline in 15-30 minutes[vii].
  • Sample (urine or serum) must be kept chilled[xi].
  • In addition to mast cells, histamine is also released by basophils. Consumption of foods or liquids that contain histamine can also inflate the level when tested[ix].
  • A recent retrospective study of almost 200 patients found that n-methylhistamine was elevated in 7.4% of MCAS patients in random spot urine and 5.4% in 24-hour urine[xi].
  • Sensitivity of 24-hour n-methylhistamine for MCAS was assessed as 22% in 24-hour urine[ix].
  • Plasma histamine was elevated in 29.3% of MCAS patients[xi].
  • 50-81% of systemic mastocytosis patients demonstrate elevated n-methylhistamine in 24-hour urine[ix].

Prostaglandin D2 and degradation product prostaglandin 9a,11b-F2

  • 9a,11b-prostaglandin F2 is the breakdown product of prostaglandin D2.
  • Prostaglandin D2 is only produced in large quantities by mast cells. Basophils, eosinophils and other cells produce minute amounts[ix].
  • A recent retrospective study of almost 200 patients found that PGD2 was elevated in 9.8% of MCAS patients in random spot urines and 38.3% in 24-hour urine[xi].
  • PGD2 was elevated in 13.2% of MCAS patients in plasma[xi].
  • 9a,11b-PGF2 was elevated in 36.8% in 24-hour urine[xi].
  • 62-100% of systemic mastocytosis patients demonstrate elevated prostaglandin D2 or 9a,11b-PGF2 in urine[ix].
  • Prostaglandins are thermolabile and begin to break down in a minutes. This can contribute to false negative results[xi].
  • Medications that inhibit COX-1 and COX-2, such as NSAIDs, decrease prostaglandin production[xi].

Leukotriene E4

  • Leukotriene E4 is produced by mast cells and several other cell types[ix] including eosinophils, basophils and macrophages.
  • A recent retrospective study of almost 200 patients found that LTE4 was elevated in 4.4 % of MCAS patients in random spot urines and 8.3% in 24-hour urine[xi].
  • 44-50% of systemic mastocytosis patients demonstrate elevated leukotriene E4 in urine[ix].
  • Medications that inhibit 5-LO, such as lipoxygenase inhibitors, decrease leukotriene production[xii].

Chromogranin A

  • Chromogranin A is produced by mast cells and several other cell types including chromaffin cells and beta cells.
  • Proton pump inhibitors can cause increased values during testing[xi].
  • A 2014 paper reported chromogranin A was elevated in 12% of MCAS patients and 63% of systemic mastocytosis patients tested[ix].


  • Heparin is a very specific mediator for mast cell activation[ix].
  • Heparin is extremely heat sensitive. The sample must be kept on ice or refrigerated at all times[ix].
  • Venous occlusion of upper arm for ten minutes has been successful in provoking mast cell activation leading to heparin release[ix].
  • A 2014 paper reported plasma heparin was elevated in 59% of MCAS patients and 47% of systemic mastocytosis patients tested[ix].
  • A recent retrospective study of almost 200 patients found that plasma heparin was elevated in 28.9% tested[ix].



[i] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.

[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[iv] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.

[v] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.

[vi] Payne V, Kam PCA. (2004). Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia, 59(7), 695-703.

[vii] Phadia AB. ImmunoCAP® Tryptase in anaphylaxis. Retrieved from:

[viii] Sprung J, et al. (2015). Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology, 122(3), 713-717.

[ix] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912

[x] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).

[xi] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.”  Mast Cells, edited by David B. Murray, Nova Science Publishers, Inc., 2013, 155-231.

[xii] Hui KP, et al. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax, 46, 184-189.

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

Skin symptoms    
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels

Blood is closer to the skin and redness is seen

Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of skin

Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of tissue


Respiratory symptoms    
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production

Smooth muscle constriction


Cardiovascular symptoms    
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF,  PGD2, bradykinin Decreased force of heart contraction

Increased vasodilation and permeability of blood vessels

Impact on norepinephrine signaling

Change in heart rate

Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels

Decrease in blood pressure

Dysfunctional release of neurotransmitters

High blood pressure Chymase,  9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

Tightening and decreased permeability of blood vessels

Tachycardia Histamine (H2), PGD2 Increasing heart rate

Increasing force of heart contraction

Impact on norepinephrine signaling

Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway

Impact on norepinephrine signaling


Gastrointestinal symptoms    
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction

Increased gastric acid secretion

Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters


Cardiovascular manifestations of mast cell disease: Part 5 of 5

Low blood pressure causing lightheadedness or fainting is a classic manifestation of mast cell disease with as many as 22-55% of patients having experienced it at least one. For comparison, the control group demonstrated a frequency of 5%.  Some patients experience this symptom often while others only rarely experience it or never do.

A staggering amount of mast cell mediators can induce low blood pressure; indeed, this is the reason why low blood pressure is the hallmark sign of severe allergic reaction and anaphylaxis.  Histamine can induce hypotension through the H1 receptor.  Heparin makes histamine and tryptase less susceptible to degradation, allowing longer action.

Many mediators are vasodilating, widening the blood vessels. Vasoactive intestinal peptide (VIP) is a vasodilator.  PGD2 is also a very potent in this capacity. PGE2 is not released in large amounts by mast cells, but has the same effect. Platelet activating factor decreases blood pressure in multiple ways: by decreasing the force of heart muscle contraction, by slowing heart rate and by widening blood vessels. IL-6 and nitric oxide are also vasodilating.

Some mediators lower blood pressure by their participation in the bradykinin pathway.  Bradykinin is a potent stimulator of fluid loss from the blood to the tissues, causing low blood pressure and angioedema. Heparin can serve as an initiator for the production of bradykinin. Tryptase and chymase both participate in bradykinin formation.

Mast cell medications can be very effective in increasing blood pressure by decreasing fluid loss from the blood to the tissues.  As PGD2 can be a strong vasodilator, COX inhibitors like NSAIDs that interfere with prostaglandin production can help to increase blood pressure.  Aspirin, 81-325mg once or twice daily, is sometimes recommended for adults that are not sensitive to the medication.  Early data on the use of omalizumab (Xolair) in SM patients indicates that it may prevent episodes of sudden onset low blood pressure.


Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.


Cardiovascular manifestations of mast cell disease: Part 3 of 5

Recurrent or perpetual elevation in blood pressure has been observed in multiple studies and may affect up to 31% of patients with mast cell activation disease (systemic mastocytosis, mast cell activation syndrome/disorder, monoclonal mast cell activation syndrome). Despite this high prevalence, many providers continue to believe that this symptom cannot be inherently from mast cell activation.

A number of mast cell mediators are vasoconstrictors, narrowing the blood vessels and elevating blood pressure. Histamine can both increase and lower blood pressure depending on which receptor it acts upon (H1: hypotension; H2: hypertension).

Several mediators participate in the angiotensin-renin pathway. Angiotensin II, the level of which is largely determined by mast cell mediators like renin, strongly elevates blood pressure. Chymase, involved in the angiotensin-renin pathway, can also either increase or lower blood pressure depending on concentration relative to other mediators present. Carboxypeptidase A can also affect angiotensin II level as well. Renin regulates the level of a molecule that becomes angiotensin II and can increase blood pressure this way.

Phospholipases, which help produce the molecule needed to make prostaglandins, leukotrienes and thromboxanes can contribute to either high or low blood pressure depending upon which molecule is made. Prostaglandin D2 (PGD2) is a vasodilator, lowering blood pressure; but its metabolite, 9a,11b-PGF2, increases blood pressure. (Author’s note: I personally believe this to be the reason for the rapid blood pressure fluctuations in mast cell patients, but do not have evidence to directly support this.) Thromboxane A2, a molecule related to prostaglandins and leukotrienes, increases blood pressure, as do leukotrienes.

Management of high blood pressure is complicated in mast cell patients by the interaction of common antihypertensives with mast cell activation. Beta blockers are contraindicated in mast cell patients because they interfere with epinephrine, both naturally produced and medicinally.  Use of beta blockers is a risk factor for fatal anaphylaxis.  Any patient on beta blockers that carries an epipen should also carry a glucagon pen, which can be administered prior to the epipen to increase efficacy.

ACE inhibitors interfere with angiotensin converting enzyme, which increases blood pressure through the angiotensin II pathway.  ACE inhibitors affect bradykinin levels, a mast cell mediator that is also mast cell activating.  For this reason, ACE inhibitors can increase mast cell reactivity and symptoms like angioedema.

Author’s note:  I extended this series to four posts to discuss heart failure in mast cell patients.  Following this series, I will be posting a series dedicated exclusively to Kounis Syndrome, including diagnosis and treatment.  Sit tight!


Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.


Cardiovascular manifestations of mast cell disease (Part 2 of 5)

Abnormalities of heart rate and rhythm can occur due to action of several mast cell mediators. Histamine binds at histamine receptors numbered in the order of identification: H1, H2, H3 and H4. Histamine binding at H1 receptors on cardiomyocytes (heart muscle cells) slows the heart rate, while histamine binding at H2 receptors increasing heart rate and the force of heart contraction.

As I mentioned in the previous post, histamine binding at the H3 receptor decreases the release of norepinephrine. Another mast cell product, renin, modulates angiotensin II, which can increase norepinephrine release.  Increased levels of norepinephrine triggers increases in heart rate and force of contraction.  This means that whether or not mast cell activation causes tachycardia depends largely on how much renin and histamine are released. Much less histamine is necessary to trigger the H3 inhibition of norepinephrine release relative to the amount needed to affect heart rate through H1 and H2 receptors.

Prostaglandin D2, a mast cell mediator, can also cause tachycardia.  Of note, prostaglandin D2 is not stored in mast cell granules.  It is made following mast cell activation and is considered part of the “late phase allergy response”, which can occur several hours after exposure to a trigger.

Tachycardia is a common symptom for mast cell patients.  The recommendation in a recent review article is to treat when the heart rate is perpetually over 100-120 bpm, or when it is extremely distressing to the patient. There are a number of options for treatment. As it can be caused directly by mast cell behavior, mast cell medications such as antihistamines (H1 and H2) should be adjusted for maximum effect. Renin inhibitors, such as aliskiren (Tekturna in the US), can be used to treat supraventricular tachycardia (SVT) in mast cell patients, as can angiotensin receptor blockers like losartan, valsartan and others. Patients on renin inhibitors or angiotensin receptor blockers can also decrease blood pressure.

Calcium channel blockers, like verapamil, are also an option.  The medication ivabradine treats tachycardia in patients who have a regular heart rhythm and does not affect blood pressure.  Ivabradine is not used to treat atrial fibrillation. β-blockers are contraindicated in mast cell patients because it interferes with the action of epinephrine, making patients more likely to have reactions and epinephrine less likely to treat effectively.


Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

Master table of de novo mast cell mediators


Mediator Symptoms Pathophysiology
b-FGF (basic fibroblast growth factor) Angiogenesis, proliferation, wound healing, binds heparin
GM-CSF (granulocyte macrophage colony stimulating factor) Rheumatoid arthritis Induces stem cells to make granulocytes and monocycles
IL-1a Fever, insulin resistance, inflammatory pain Activates TNFa, stimulates production of PGE2, nitric oxide, IL-8 and other chemokines
IL-1b Pain, hypersensitivity Autoinflammatory syndromes, regulates cell proliferation, differentiation and death, induces COX2 activity to produce inflammatory molecules
IL-2 Itchiness, psoriasis Regulates T cell differentiation
IL-3 Drives differentiation of several cell types, including mast cells, and proliferation
IL-4 Airway inflammation, allergic asthma Regulates T cell differentiation
IL-5 Eosinophilic allergic disease Activates eosinophils, stimulates proliferation of B cells and antibody secretion, heavily involved in eosinophilic allergic disease
IL-6 Fever, acute phase inflammation, osteoporosis Inhibits TNFa and IL-1, stimulates bone resorption, reduces inflammation in muscle during exercise
IL-9 Asthma, bronchial hypersensitivity Increases cell proliferation and impedes apoptosis of hematopoietic cells
IL-10 Regulates the JAK-STAT pathway, interferes with production of interferons and TNFa.   Exercise increases levels of IL-10
IL-13 Airway disease, goblet cell metaplasia, oversecretion of mucus Induces IgE release from B cells, links allergic inflammation to non-immune cells
IL-16 Allergic asthma, rheumatoid arthritis, Crohn’s disease Attracts activated T cells to inflamed spaces,
IL-18 Linked to several autoimmune and inflammatory conditions, including Hashimoto’s thyroiditis Induces release of interferon-g, causes severe inflammatory reactions
Interferon-a Flu like symptoms, malaise, muscle soreness, fever, sore throat, nausea Inhibition of mast cell growth and activity
Interferon-b Flu like symptoms, malaise, muscle soreness, fever, sore throat, nausea Inhibition of mast cell growth and activity
Interferon-g Granuloma formation, chronic asthma Induces production of nitric oxide, IgG2a and IgG3 from B cells, increases production of histamine, airway reactivity and inflammation
Leukotriene B4 Mucus secretion, bronchoconstriction, vascular instability, pain Draws white cells to site of inflammation
Leukotriene C4 Mucus secretion, bronchoconstriction, vascular instability, pain Draws white cells to site of inflammation
MCP-1 Neuroinflammation, diseases of neuronal degeneration, glomerulonephritis Draws white blood cells to inflamed spaces,
MIF (macrophage migration inhibitory factor) Regulate acute immune response, release triggered by steroids
MIP-1a (macrophage inflammatory protein) Fibrosis Activates granulocytes, nduces release of IL-1, IL-6 and TNFa
Neurotrophin-3 Nerve growth factor
NGF (nerve growth factor) Regulates survival and growth of nerve cells, suppresses inflammation
Nitric oxide Bruising, hematoma formation, excessive bleeding Vasodilation, inhibition of platelet aggregation
PDGF (platelet derived growth factor) Platelet growth factor, growth of blood vessels, wound healing
Platelet activating factor Constriction of airway; urticaria; pain Platelet activation and aggregation, vasodilation
Prostaglandin D2 Flushing, mucus secretion, bronchoconstriction, vascular instability, mixed organic brain syndrome, nausea, abdominal pain, neuropsych symptoms, nerve pain Inflammation, pain, bronchoconstriction
Prostaglandin E2 Muscle contractions, cough Draws white blood cells to site of inflammation
RANTES (CCL5) Osteoarthritis Attracts white cells to inflamed spaces, causes proliferation of some white cells
SCF (stem cell factor) Regulates mast cell life cycle, induces histamine release
TGFb (transforming growth factor beta) Bronchial asthma, heart disease, lung fibrosis, telangiectasia, Marfan syndrome, vascular Ehlers syndrome syndrome Regulates vascular and connective tissues
TNFa (tumor necrosis factor) Fever, weight loss, fatigue Regulates death of cells and acute inflammation
VEGF (vascular endothelial growth factor) Bronchial asthma, diabetes Angiogenesis, draws white cells to inflamed spaces, vasodilation



Exercise and mast cell activity

Research on exercise induced bronchoconstriction represents a large body of work through which we can draw conclusions about mast cell behavior as affected by exercise.

Exercise has been found in a number of studies to induce mast cell degranulation and release of de novo (newly made) mediators. One study found that levels of histamine, tryptase and leukotrienes were increased following exercise in sputum of people with exercise induced bronchoconstriction. This same study found that in these patients, prostaglandin E2 and thromboxane B2 was decreased in sputum. Treating with montelukast and loratadine suppressed release of leukotrienes and histamine during exercise.

One important area of research is the interface between being asthmatic and being obese. Adipose tissue is known to release inflammatory molecules called adipokines. In particular, the adipokine leptin has been studied for its role in bronchoconstriction following exercise. Leptin (I did a previous post on leptin, which is also called the obesity hormone) enhances airway reactivity, airway inflammation and allergic response. It can also enhance leukotriene production. This last fact is interesting because obese asthmatics are less likely to respond to inhaled corticosteroids when compared to lean asthmatics, but both respond similarly to anti-leukotriene medications like montelukast.

LTE4 was found to be significantly higher in the urine of both obese and lean asthmatics following exercise. It was not increased in either obese non-asthmatics or healthy controls. Additionally, the level of LTE4 was significantly higher in obese asthmatics compared to lean asthmatics. In this same study, urinary 9a, 11b-PGF2 was elevated in both lean and obese asthmatics, but not in obese or healthy controls. The 9a, 11b-PGF2 level was also higher in obese asthmatics than lean asthmatics. The elevated LTE4 and 9a, 11b-PGF2 were found in urine testing rather than in sputum, indicating that these chemicals did not stay local to the lungs and airway.

It is thought that the high levels of leptin found in asthmatics drive the manufacture and release of leukotrienes and prostaglandins from mast cells, epithelial cells or eosinophils during exercise. Though the data are stacking up to look like this is the case, there has not yet been a definitive causal link established.



Teal S. Hallstrand, Mark W. Moody, Mark M. Wurfel, Lawrence B. Schwartz, William R. Henderson, Jr., and Moira L. Aitken. Inflammatory Basis of Exercise-induced Bronchoconstriction. American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 6 (2005), pp. 679-686.

Hey-Sung Baek, et al. Leptin and urinary leukotriene E4 and 9α,11β-prostaglandin F2 release after exercise challenge. Volume 111, Issue 2, August 2013, Pages 112–117


Mast cell mediators: Prostaglandin D2 (PGD2)

Prostaglandin D2 (PGD2) is the predominant prostaglandin product released by mast cells. It is found prevalently in the central nervous system and peripheral tissues, where it performs both inflammatory and normal processes. In the brain, PGD2 helps to regulate sleep and pain perception. PGD2 can be further broken down into other prostaglandins, including PGF2a; 9a, 11b-PGF2a (a different shape of PGF2a), and forms of PGJ. 9a, 11b-PGF2a shares the same biological functions as PGD2. Both of these can be tested for in 24 hour urine test as markers of mast cell disease.

PGD2 is a strong bronchoconstrictor. It is 10.2x more potent in this capacity than histamine and 3.5x more potent than PGF2a. It has been associated with inflammatory and atopic conditions for many years. Presence of allergen activates PGD2 production in sensitized people. In asthmatics, bronchial samples can achieve over 150x the level of PGD2 compared to controls. Elevated PGD2 has been associated with chronic coughing.

PGD2 is a driver of inflammation in many settings. It acts on bronchial epithelium to cause production of chemokines and cytokines. It also brings lymphocytes and eosinophils to the airway, which induces airway inflammation and hyperreactivity in asthmatics. PGD2 may also inhibit eosinophil cell death, resulting in further inflammation.

An interesting facet of PGD2 is its role in nerve pain. It has been found that PGD2 is produced by microglia in the spine after a peripheral nerve injury. These cells make more COX-1, which then makes PGD2. Newer COX-2 inhibiting NSAIDs do not affect nerve pain in mouse models, but older NSAIDs that inhibit COX-1 and COX-2 reduce neuropathy.

PGD2 is found to inhibit inflammation in other settings. It can reduce eosinophilia in allergic inflammation in mouse models. Additionally, once the acute phase of inflammation is over and it is resolving, administering a COX-2 inhibitor actually makes the inflammation worse. This indicates that PGD2 may be important in resolving inflammation in some processes.

Aspirin is commonly used in mast cell patients to inhibit prostaglandin production. PGD2 is primarily manufactured by COX-2, but the pathway that evokes neuropathy uses COX-1. There are a number of COX-1 and COX-2 inhibitors available.

In mast cell patients, PGD2 is probably most well known for causing flushing. This happens due to dilation of blood vessels in the skin. Due to a well characterized response to aspirin, this is generally the first line medication choice. Some salicylate sensitive mast cell patients undergo aspirin desensitization to be able to use this medication.



Emanuela Ricciotti, Garret A. FitzGerald. Prostaglandins and Inflammation. Arterioscler Thromb Vasc Biol. 2011; 31: 986-1000.

Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S. Prostaglandin D2 as a mediator of allergic asthma. Science. 2000;287: 2013–2017.

G Bochenek, E Nizankowska, A Gielicz, M Swierczynska, A Szczeklik. Plasma 9a,11b-PGF2, a PGD2 metabolite, as a sensitive marker of mast cell activation by allergen in bronchial asthma. Thorax 2004; 59: 459–464.

Victor Dishy, MD, Fang Liu, PhD, David L. Ebel, BS, RPh, George J. Atiee, MD, Jane Royalty, MD, Sandra Reilley, MD, John F. Paolini, MD, PhD, John A. Wagner, MD, PhD, and Eseng Lai, MD, PhD. Effects of Aspirin When Added to the Prostaglandin D2 Receptor Antagonist Laropiprant on Niacin-Induced Flushing Symptoms. Journal of Clinical Pharmacology, 2009; 49: 416-422

MCAS: Neurologic and psychiatric symptoms

The neuropsychiatric symptoms associated with MCAS are numerous and are results of the chemicals released by mast cells.

Headaches are a very common complaint. They can sometimes be managed with typical remedies (Excedrin, Tylenol) and antihistamine treatment often helps with this symptom quickly. However, in some patients, headaches can be disabling. Diagnosis of migraine is not unusual, with mast cell degranulation having been tied previously to migraines.

Dizziness, lightheadedness, weakness, vertigo, and the feeling of being about to faint are all typical in MCAS, though true fainting spells are less common than in mastocytosis. These symptoms often cause many MCAS patients to be diagnosed with dysautonomia or POTS.

MCAS patients often experience increased activation of sensory and motor nerves. This manifests as generic neurologic symptoms, sometimes several at once, like tingling, numbness, paresthesia and tics. Tics generally do not spread from the place they initially present. Paresthesias seem to progress for a period of time, then wane and disappear. Extremities are most commonly affected.

EMG and nerve conduction studies are typically normal or abnormal in a way that is not diagnostic. These tests sometimes reflect a possibility of chronic inflammatory demyelinating polyneuropathy (CIDP.) These patients also sometimes are positive for monoclonal gammopathy of unknown significance (MGUS), a blood marker that has been tied to multiple myeloma. However, in these patients, the MGUS is believed to be an effect of the MCAS.

Another subset of patients are diagnosed with subacute combined degeneration (SCD), a deterioration of the spinal cord associated with B12 deficiency. They are sometimes treated for pernicious anemia despite lack of hematologic support for this diagnosis.

Prostaglandin D2 is a known effector of nerve damage and has been blamed for many of the neurologic symptoms seen in MCAS. Astrogliosis, abnormal proliferation of astrocytes (nerve cells in the brain), and demyelination (loss of the insulating cover for nerves that allows the body to send signals) are markers of neurodegeneration. These factors cause scarring and inhibit nerve repair mechanisms. PGD2 is made by an enzyme called hematopoietic PGD synthase. In mice that don’t make this enzyme, these kinds of neuroinflammation are suppressed. Treatment of normal mice with an inhibitor of this enzyme (HQL-72) also decreases these actions. This indicates that PGD2 is critical in causing neuroinflammation including demyelination. PGD2 also activates pain receptors strongly, causing sometimes profound neurologic pain.

PGD2 is also the most potent somnagen known, meaning that it induces sleep more strongly than any other molecule. MCAS patients report inordinately deep sleep, “mast cell coma.” This is likely due to excessive PGD2. Conversely, some MCAS patients also have insomnia, from excessive histamine.

I have written at length before about cognitive and psychiatric manifestations of mastocytosis, which are the same as in MCAS. Cognitive and mood disturbances are all kinds are reported. Brain fog, including short term memory troubles and word finding problems, is the most common symptom. Irritability, anger, depression, bipolar affective disorder, ADD, anxiety, panic disorders and even sometimes frank psychosis can present. Such symptoms in mastocytosis patients were referred to as mixed organic brain syndrome, a term coined in 1986. The important aspect of these symptoms in MCAS is that they are caused by mast cell activation. As such, they are most effectively treated by managing mast cell release symptoms. Some patients do find relief in some psychiatric medications, but the psychiatrist should be aware that these symptoms are part of mast cell pathology.

Additionally, PTSD is not rare in MCAS patients. This is most often due to the trauma from negative interactions with the medical industry.

Autism is significantly increased in patients with mastocytosis. Similar findings are beginning to surface with MCAS patients. Interesting, most autism spectrum disorder patients have food intolerance and general allergic symptoms. A future post will discuss this in more detail.


Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2013. Mast cells.

Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011;4:10-17.

Ikuko Mohri, Masako Taniike, Hidetoshi Taniguchi, Takahisa Kanekiyo, Kosuke Aritake, Takashi Inui, Noriko Fukumoto, Naomi Eguchi, Atsuko Kushi, Hitoshi. Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in twitcher. The Journal of Neuroscience, April 19, 2006 • 26(16):4383– 4393.

Rogers MP, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med. 1986 Jul-Aug;48(6):437-47.