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

 

Gynecologic symptoms    
Symptom Mediators Mechanism
Irregular and painful menstruation Histamine (H1), bradykinin Smooth muscle constriction
Uterine contractions Histamine (H1), serotonin, bradykinin Smooth muscle constriction

Increased estrogen

 

 

Neurologic symptoms    
Symptom Mediators Mechanism
Appetite dysregulation Histamine (H1), histamine (H3), leptin Dysfunctional release of neurotransmitters, suppression of ghrelin
Disorder of movements Histamine (H2), histamine (H3) Dysfunctional release of neurotransmitters, increases excitability of cholinergic neurons
Memory loss Histamine (H1), histamine (H3) Dysfunctional release of neurotransmitters
Headache Histamine (H1), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

Low serotonin

 

Decreased blood flow to brain

Depression Serotonin (low), TNF, histamine (H1) Low serotonin

Disordered release of dopamine

Irregular sleep/wake cycle Histamine (H1), histamine (H3), PGD2 Dysfunctional release of neurotransmitters
Brain fog Histamine (H3), inflammatory cytokines Dysfunctional release of neurotransmitters, neuroinflammation
Temperature dysregulation Histamine (H3) Dysfunctional release of neurotransmitters, dysfunctional release of catecholamines

 

 

Miscellaneous symptoms    
Symptom Mediators Mechanism
Bleeding diathesis (tendency to bleed easily) Tryptase, heparin Participation in anticoagulation pathways

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

 

Master table of stored mast cell mediators

Mediator Symptoms Pathophysiology
Angiogenin Tissue damage Formation of new blood vessels, degradation of basement membrane and local matrix
Arylsulfatases Breaks down molecules to produce building blocks for nerve and muscle cells
Bradykinin Angioedema, swelling of airway, swelling of GI tract, inflammation, pain, hypotension Vasodilation, induces release of nitric oxide and prostacyclin
Carboxypeptidase A Muscle damage Tissue remodeling
Cathepsin G Pain, muscle damage Converts angiotensin I to II, activates TGF-b, muscle damage, pain, fibrosis, activates platelets, vasodilation
Chondroitin sulfate Cartilage synthesis
Chymase Cardiac arrhythmia, hypertension, myocardial infarction Tissue remodeling, conversion of angiotensin I to II, cleaves lipoproteins, activates TGF-b, tissue damage, pain, fibrosis
Corticotropin-releasing hormone Dysregulation has wide reaching and severe effects Stimulates secretion of ACTH to form cortisol and steroids
Endorphins Numbness Pain relief
Endothelin Hypertension, cardiac hypertrophy, type II diabetes, Hirschsprung disease Vasoconstriction
Eotaxin (CCL11) Cognitive deficits Attracts eosinophils, decreases nerve growth
Heparin Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers Cofactor for nerve growth factor, anticoagulant, prevents platelet aggregation, angiogenesis
Histamine Headache, hypotension, pruritis, urticaria, angioedema, diarrhea, anaphylaxis Vasodilation of vessels, vasoconstriction of atherosclerotic coronary arteries, action of endothelium, formation of new blood vessels cell proliferation, pain
Hyaluronic acid Degradation contributes to skin damage Tissue repair, cartilage synthesis, activation of white blood cells
IL-8 (CXCL8) Mast cell degranulation Attracts white blood cells (mostly neutrophils) to site of infection, activates mast cells, promotes degranulation
Kininogenases Angioedema, pain, low blood pressure Synthesis of bradykinin
Leptin Obesity Regulates food intake
Matrix metalloproteinases Irregular menses (MMP-2) Tissue damage, modification of cytokines and chemokines (modifies molecules to make them useful)
MCP-1 (CCL2) Nerve pain Attracts white blood cells to site of injury or infection, neuroinflammation, infiltration of monocytes (seen in some autoimmune diseases)
MCP-3 (CCL7) Increases activity of white blood cells in inflamed spaces
MCP-4 (CCL13) Shortness of breath, tightness of airway, cough Attracts white blood cells to inflamed spaces, induces mast cell release of TNFa and IL-1, asthma symptoms
Phospholipase A2 Vascular inflammation, acute coronary syndrome Generates precursor molecule for prostaglandins and leukotrienes
RANTES (CCL5) Osteoarthritis Attracts white cells to inflamed spaces, causes proliferation of some white cells
Renin Cardiac arrhythmias, myocardial infarction, blood pressure abnormalities Angiotensin synthesis, controls volume of blood plasma,lymph and interstitial fluid, regulates blood pressure
Serotonin/5-HT Nausea, vomiting, diarrhea, headache, GI pain Vasoconstriction, pain
Somatostatin Low stomach acid symptoms, low blood sugar Regulates endocrine system, cell growth and nerve signals, inhibits release of glucagon and insulin, decreases release of gastrin, secretin and histamine
Substance P Neurologic pain, inflammation, nausea, vomiting, mood disorders, anxiety Transmits sensory nerve signals, including pain, mood disorders, stress perception, nerve growth and respiration
Tissue plasminogen activator Blood clots Activates plasminogen, clotting
Tryptase Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers; inflammation Activation of endothelium, triggers smooth muscle proliferation, activates degradation of fibrinogen, activates MMP molecules,tissue damage, activation of PAR, inflammation, pain
Urocortin Increased appetite when stressed, inflammation, low blood pressure Vasodilation, increases coronary blood flow
Vasoactive intestinal peptide Decreased absorption, low blood pressure, low stomach acid symptoms Vasodilation, mast cell activation, lowers blood pressure, relaxes muscles of trachea, stomach and gall bladder, inhibits gastric acid secretion, inhibits absorption
VEGF Diseases of blood vessels Formation of new blood vessels, vasodilation and permeability of smaller vessels

Histamine effects on neurotransmitters (serotonin, dopamine and norepinephrine)

Some of the most important actions of histamine involve regulation of neurotransmitters.  Release of acetylcholine, norepinephrine and serotonin are all controlled in part by histamine levels.  Injection of histamine into the hypothalamus increased metabolism of norepinephrine and serotonin, while dopamine metabolism increased in some places and not in others.  Medications that block the H1 receptor increase dopamine release.  Histamine stimulates prolactin release via the H2 receptor, which in turn inhibits dopamine production.  Histamine can locally increase the concentration of norepinephrine.

Serotonin is a neurotransmitter.  This means that cells nerve cells use this to communicate.  Most of the serotonin in the body is found in the GI tract, where it controls the way the intestine moves food through it.  However, one study indicated that as much as 40% of serotonin in the human body could originate in mast cells.  Serotonin is metabolized to 5-HIAA, which can be tested for as a sign of mast cell activation.
Serotonin released in the GI tract eventually enters the blood stream. On its way to the blood stream, it is taken up by platelets and later used in clotting.   Serotonin is released when eating, which decreases dopamine release and decreases appetite.  If the food consumed is irritating to the GI tract, more serotonin is secreted to move it through the gut faster.  In these situations, the serotonin cannot be fully taken up by platelets and enters the blood stream as free serotonin.  When this happens, it stimulates vomiting.  Some foods contain serotonin, but it does not cross the blood brain barrier and thus does not affect brain chemistry. 
Mast cells contain dopamine, a hormone and neurotransmitter.  This chemical is most often associated with reward seeking behavior, including addiction behaviors.  It also has other important roles, including motor functions.  Mast cell activation causes depletion of dopamine as frequent degranulation causes a decrease in dopamine production by these cells.   Dopamine can be converted to norepinephrine.
In blood vessels, dopamine inhibits norepinephrine release and acts as vasodilator.  Dopamine also increases sodium excretion and urine output, reduces insulin production, reduces GI motility, protects intestinal mucosa and reduces activity of lymphocytes.  It is responsible for cognitive alertness.  If you consider that high histamine levels can decrease dopamine levels, this means that in a mast cell patient, low dopamine levels might cause decreased urine output, increased GI motility and overactivation of white blood cells.  Additionally, low dopamine can translate into higher than normal norepinephrine levels, which could be the link between mast cell disease and POTS.  Brain fog and decreased alertness are effects of low dopamine.
Defective transmission of dopamine is also found in painful conditions like fibromyalgia and restless legs syndrome, associated with mast cell disease.  Activation of D2 dopamine receptors causes nausea and vomiting.  Metoclopramide is a D2 inhibitor and achieves its anti-nausea effects through this mechanism. (Note: metoclopramide can inhibit histamine metabolism and for this reason is not recommended for mast cell patients.)  Some dopaminergic drugs like clozapine, bromocriptine and haloperidol inhibit mast cell degranulation.
Norepinephrine is responsible for concentration and vigilance.  It also increases vascular tone by action on alpha adrenergic receptors.  Norepinephrine is important in the fight or flight response, directly increasing heart rate, triggering release of glucose, increasing blood flow to skeletal muscle and increasing brain oxygen supply.  Interestingly, fasting increases norepinephrine for days.  Glucose intake, but not carbohydrate or protein intake, also increases norepinephrine.  Increased histamine can cause increases in norepinephrine production and secretion.