https://doi.org/10.1080/1744666X.2019.1596800

Comment; Excellent overview of the evolving state of understanding of Mast Cell Disorders as well as lists of the Symptoms divided by Organ Systems, Co-Morbid conditions involving mast cells, Triggers of Mast Cells with and without full degranulation, Mediators contained in mast cells, Diagnostic Criteria for mast cell disorders and most importantly, treatment options.

Theoharis C. Theoharides, Irene Tsilioni & Huali Ren

Expert Review of Clinical Immunology, DOI: 10.1080/1744666X.2019.1596800

Introduction: An increasing number of patients present with multiple symptoms affecting many organs including the brain due to multiple mediators released by mast cells. These unique tissue immune cells are critical for allergic reactions triggered by IgE, but are also stimulated (not activated) by immune, drug, environmental, food, infectious, and stress triggers, leading to secretion of multiple mediators often without histamine and tryptase. The presentation, diagnosis and management of the spectrum of mast cell disorders is very confusing. As a result, specialists have recently excluded neuropsychiatric symptoms, and made the diagnostic criteria stricter, at the expense of excluding most patients.

Areas covered: A literature search was performed on papers published between January 1990 and November 2018 using MEDLINE. Terms used were activation, antihistamines, atopy, autism, brain fog, heparin, KIT mutation, IgE, inflammation, IL-6, IL-31, IL-37, luteolin, mast cells, mastocytosis, mediators, myalgic encephalomyelitis/chronic fatigue syndrome, mycotoxins, release, secretion, tetramethoxyluteolin, tryptase.

Expert commentary: Conditions associated with elevated serum or urine levels of any mast cell mediator, in the absence of any comorbidity that could otherwise explain such increases, should be considered mast cell activation disorders, or better yet be collectively termed “Mast Cell Mediator Disorders (MCMD)”. Emphasis should be placed on the identification of unique mast cell mediators, and development of drugs or supplements that inhibit their release.

Common Symptoms in Patients With Mast Cell Mediator Disorders   

• Cardiovascular: chest pain, hypotension, hypotensive syncope, tachycardia

• Dermatologic: angioedema, dermatographism, flushing, pruritus, urticaria pigmentosa

• Gastrointestinal: abdominal crumping/pain, bloating, diarrhea, esophagitis, nausea, vomiting 

• Musculoskeletal: bone/muscle pain, degenerative disc disease, osteoporosis/ osteopenia

• Naso-ocular: nasal congestion, pruritus, tearing

• Neurologic: headache, memory and concentration difficulties (brain fog), paresthesias, peripheral neuropathy 

• Respiratory: hoarseness, sore throat, stridor, throat swelling, wheezing

• Systemic: anaphylaxis, fatigue

Conditions Often Comorbid With Mast Cell Diseases

• Chronic inflammatory response syndrome (CIRS)

• Fibromyalgia syndrome (FMS)

• Ehlers-Danlos Syndrome (EDS)

• Gulf War Illness (GWI)

• Interstitial cystitis/bladder pain syndrome (IC/BPS)

• Irritable bowel syndrome (IBS)

• Kounis syndrome

• Multiple chemical sensitivity syndrome (MCSS)

• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

• Post-Lyme syndrome

• Postural orthostatic tachycardia syndrome (POTS)

• Post-traumatic stress disorder (PTSD)

Cell Triggers of Mast Cell Degranulation

Acetylcholine

Complement fragments 

– C3α, C4α, C5α

Drugs

– Local anesthetics

– Lactam antibiotics

– Neuromuscular junction blockers

– Vancomycin

IgE

IgG1

IgG4

Lysophosphatidylserine

Peptides

– Adrenomedullin

– CGRP

– Endorphin

– Endothelin

– Eosinophil granule proteins

– Hemokinin-1

– Leptin

– Mastoparan

– Neurotensin

– NGF

– PTH

– Somatostatin

– SP

– Thrombin

– VIP

Physical conditions

– Cold

– Heat

– Pressure

– Stress

– Vibration

Triggers of Mast Cells Without Degranulation

Triggers Mediator
  Peptides  
  CRH VEGF
  SCF IL-6
Cytokines  
  IL-1β IL-6
  IL-33 IL-31
  IL-33 CX CL8 (IL-8)
  IL-33 + SP TNF, VEGF
Heavy metals  
  Aluminum  
  Cadmium  
  Mercury  
Herbicides  
  Atrazine  
  Glyphosate  
Pathogens  
  Borrelia (Lyme disease) * TNF
  LPS TNF
  Poly (I:C) (viruses) IL-6, TNF
  Sporothrix (mold)* IL-6, TNF
*Mycotoxins  

Mediators found in Mast Cells

Prestored De novo synthesized
Biogenic Amines Chemokines
 Dopamine IL-8 (CXCL8), MCP-1 (CCL2), MCP-3 (CCL7),                
 Histamine MCP-4, RANTES (CCL5), Eotaxin (CCL11)
 5-Hydroxytryptamine (5-HT, serotonin) Cytokines
Polyamines  IL-1β, IL-4, IL-5, IL-6, IL-15, IL-17, IL-31, IL-33, TNF
 Spermidine, spermine Growth Factors
Cytokines SCF, β-FGF, neurotrophin 3, NGF,
 TNF PDGF, TGFβ, VEGF
Enzymes Nitric oxide
Arylsulfatases A Phospholipid metabolites
Beta-hexosaminidase  Leukotriene B4
Beta-glucuronidase  Leukotriene C4
Beta-glucosaminidase  Platelet activating factor
Beta-D-galactosidase  Prostaglandin D2
Carboxypeptidase A  
Cathepsins B, C, D, E, L  
 Chymase  
 Garnzyme B  
 Kinogenases  
 Phospholipases  
 Renin  
 Tryptase  
 Metalloproteinases  
 (CPA3, MMP9, ADAMTSS)  
Growth factors  
 FGF  
 NGF  
 SCF  
 TGFβ  
VEGF  
Peptides   
 ACTH  
 Angiogenin  
Angiopoietin  
 Calcitonin gene-related peptide  
Corticotropin-releasing hormone  
Endorphins  
Endothelin  
Hemokinin-1  
 Kinins (bradykinin)  
Leptin  
Melatonin  
Neurotensin  
RANKL  
Somatostatin  
 Substance P  
Urocortin  
Vasoactive intestinal peptide  
Proteoglycans  
Chondroitin sulfate  
Heparan sulfate  
Heparin  
Hyaluronic acid  
Serglin  

Diagnostic Criteria for Systemic Mastocytosis

Major criterion

a. Multifocal, dense infiltrates of mast cells (≥ 15 mast cells in aggregates) detected in intramedullary biopsy sections and/or extramedullary organ(s).

Minor criteria

a. In intramedullary biopsy sections or other extramedullary ones >25% of the mast cells in the infiltrate are spindle shaped or have atypical morphology, or of all mast cells in bone marrow aspirate smears >25% are immature or atypical

b. Gain of function point mutation of KIT at codon 816 (usually KIT D816V) in bone marrow, blood or other extracutaneous organ

c. Aberrant immunophenotype of mast cells of CD2 and/or CD25 in bone marrow, blood or other extracutaneous organ (in addition to normal mast cell markers)

d. Persistently elevated baseline serum total tryptase (>20 ng/ml).

Treatment Approach for Mast Cell Mediator Disorders

1. Antihistamines (cetirizine, diphenhydramine, hydroxyzine)

2. Antihistamines with anti-eosinophilic action (ketotifen, rupatadine)

3. Antihistamine with anti-serotonin action (cyproheptadine)

4. Tricyclic antidepressants with combined antihistamine action (doxepin)

5. Flavonoids (luteolin, quercetin of high purity and increased absorption)

6. Antileukotrienes (montelukast)

7. Cromolyn sodium

8. Steroids (methylprednisolone)

9. Epinephrine (EpiPen, AnaPen)

10. Anti-IgE (omalizumab)

11. TK inhibitor (imatinib)

12. Kinase inhibitors for mast cells expressing mutant KIT (mitostaurine, avapritinib)

*Patients with migraine headaches could be helped prophylactically with cyproheptadine or with prochlorperazine, both of which also inhibit human mast cells [285]. 

Dr. Raymond Oenbrink