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

 

Chronic urticaria and angioedema: Part 4

There are a number of other conditions that present with similar features to chronic urticaria and angioedema.

Conditions that can present similarly to chronic urticaria are listed below.

Chronic urticarial vasculitis is associated with low or normal complement levels and confusingly can be a primary autoimmune disorder, or a process secondary to another autoimmune disease, like lupus. Urticarial vasculitis lesions sometimes resolve quickly but can last for several days. A lesion biopsy can distinguish between CU and chronic urticarial vasculitis. Painful or burning lesions suggest urticarial vasculitis, with raised lesions that don’t blanch, and may leave hyperpigmented areas in place of resolved lesions. Hepatitis B and C can cause urticarial vasculitis.

Swelling of the upper eyes can be mistaken for angioedema, but in some people may be a symptom of thyroid ophthalmopathy, thyroid driven eye disease. Development of urticaria for during pregnancy is not unusual. Cyclical urticaria can be from autoimmune progesterone dermatitis. Episodes of angioedema with accompanying weight gain can be caused by Gleich syndrome (episodic angioedema with eosinophilia).

Cutaneous mast cell patients demonstrate a variety of urticaria-like lesions, including urticaria pigmentosa, mastocytomas and telangiectasia macularis eruptive perstans. Mast cell activation syndrome can also cause angioedema and urticaria, but generally these are not the only symptoms.

Erythema multiforme looks like urticaria but is often due to viral infections, mycoplasma infections or some medications. Bullous pemphigoid can initially present with hive-like welts or small plaques that do not always blister in early disease. Swelling of the lips in the absence of eczema can indicate cheilitis granulomatosa.

Schnitzler syndrome can cause non-itching hives that exclude the face, bone pain and intermittent fevers. These patients also have IgM or IgG monoclonal gammopathy.

 

Angioedema in the absence of urticaria is rare. There are a few conditions that can cause it.

Hereditary angioedema (HAE) is caused by C1 esterase inhibitor deficiency (in type I, 80%-85% of cases); or dysfunction (in type II, 15-20%).  People with HAE do not have coincident urticaria. HAE is inherited in an autosomal dominant pattern, but up to ¼ of patients develop the condition through spontaneous mutation rather than through inheritance of the gene. About 40% of patients have their initial attacks before the age of 5.

Acquired angioedema (AAE) is caused by antibodies to C1 esterase inhibitor, which is usually caused by cancers of B cells. AAE is more likely to develop in older patients (usually fourth decade of life or later) and family history of angioedema is generally absent. AAE is also more likely to develop when an autoimmune disease or proliferative blood disorder is present.

Angioedema associated with these conditions can affect any part of the body, including limbs and abdomen. Patients with abdominal angioedema are often misdiagnosed as having an “acute” abdomen that requires surgical intervention. It is not unusual for patients to present initially only with abdominal swelling. Both HAE and AAE have a number of common triggers, including infection, emotional or physical stress. or trauma. Importantly, they are not caused directly by histamine and other mast cell mediators and as such are not responsive to antihistamines and corticosteroids.

There is also a form of angioedema specifically induced by treatment with ACE inhibitors. It can be relieved by discontinuing ACE inhibitor therapy.  Idiopathic angioedema can also occur in the absence of urticaria but is more likely to respond to prophylactic antihistamine use than HAE or AAE.

 

Edited to add: I removed the following line from the first HAE paragraph: “Type III is estrogen mediated and only found in adult women.”  This statement is inaccurate,  I mistakenly included i, as I had originally noted it when reading a paper from 2007.  I am doing a follow up post on HAE that will elaborate further on the different subtypes and treatment.  Many thanks to the reader who caught it!

 

References:

Jonathan A. Bernstein, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol Volume 133, Number 5.

Zuberbier T, Maurer M. Urticaria: current opinions about etiology, diagnosis and therapy. Acta Derm Venereol 2007;87:196-205.

Ferdman, Ronald M. Urticaria and angioedema. Clin Ped Emerg Med2007; 8:72-80.

Kanani, Amin, et al. Urticaria and angioedema. Allergy Asthma and Clinical Immunology 2011, 7(Suppl 1):S9.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chronic urticaria and angioedema: Part 3

There are several pathways that can culminate in angioedema and urticaria.

Activation of mast cells by IgE is the most well known mechanism. When IgE binds to receptors on mast cells, several things happen. The mast cells release histamine. This in turn causes dilation of the nearby vessels and causes fluid to leak from the bloodstream into the tissues. This causes nerve cells to activate and release substance P, which also contributes to vasodilation and causes mast cells to release more histamine. In response to activation by IgE, mast cells will also produce PGD2 and leukotrienes C4 and D4.

The complement system is one of the ways our body identifies infectious agents and triggers the immune system to kill them. Complement proteins are in the blood all the time, and they can be activated by three distinct pathways, all of which are triggered by pathogens: the classical pathway, the alternative pathway and the lectin pathway. Regardless of which pathway activates the complement system, the molecules C3a, C4a and C5a are produced. These molecules bind to receptors on mast cells and induce histamine release.

Following initial dilation of local vessels, proteins that normally are found in the plasma move into the skin. This activates the kinin system, which produces bradykinin through a series of steps. Bradykinin is a very powerful vasodilator and contributes significantly to loss of volume from the blood stream to the tissues.

C3a, C5a, PGD2, and leukotrienes C4 and D4 all draw other inflammatory cells to the site of activated mast cells. These cells release further molecules to stimulate histamine release. This mechanism perpetuates inflammation beyond the original insult.

Bradykinin levels are normally controlled by the enzyme ACE. When patients take ACE inhibitor medications (like Lisinopril, etc), this interferes with bradykinin degradation and cause urticarial and angioedema.

C1 esterase inhibitor regulates complement and kinin pathways. In patients who are deficient in C1 esterase inhibitor, bradykinin may be overproduced.

Many autoimmune conditions cause the formation of IgG1 and IgG3 antibodies. These molecules can interfere with the complement system and cause production of fragments that activate mast cells, like C3a.

NSAIDs are well characterized in their ability to cause angioedema and urticaria. While the mechanism is not fully understood, it is thought that since NSAIDs stop production of prostaglandins, the mast cells overproduce leukotrienes, which contribute to the angioedema and urticaria.

There are several non-immunologic methods that can result in angioedema and urticaria. Heat or pressure on the skin; radiocontrast dyes; alcohol; vancomycin; opioids; and foods like shellfish and strawberries have been linked to these conditions.

 

References:

Jonathan A. Bernstein, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol Volume 133, Number 5.

Usmani N,Wilkinson SM. Allergic skin disease: investigation of both immediate and delayed-type hypersensitivity is essential. Clin Exp Allergy 2007;37:1541-6.

Zuberbier T, Maurer M. Urticaria: current opinions about etiology, diagnosis and therapy. Acta Derm Venereol 2007;87:196-205.

Ferdman, Ronald M. Urticaria and angioedema. Clin Ped Emerg Med2007; 8:72-80.

 

Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system

The kinin-kallikrein system is a hormonal system with effects on inflammation, blood pressure, coagulation and pain perception. This system is known to have a significant role on the cardiovascular system, including cardiac failure, ischemia and left ventricular hypertrophy. Despite significant research, it is not entirely understood.

Kininogens are proteins that have extra pieces on them. Kininogenases cut off those extra pieces. Active kinins that can act on the body are the result of this action. So kininogenases change kininogens to form kinins.

There are two types of kininogens: low molecular weight (smaller) and high molecular weight (larger.) We are going to focus on HMW, which circulates in the blood.

Also circulating in the blood are two other components called prekallikrein (sometimes called Fletcher factor) and Hageman factor (Factor XII.) When Hageman factor lands on a negatively charged surface, it changes shape and becomes Factor XIIa. Factor XIIa changes the prekallikrein to kallikrein. Kallikrein is a kininogenase.

When kallikrein finds a kininogen, it cuts off the extra piece to release bradykinin. Bradykinin is a kinin and is ready to act on the body.

Bradykinin has several functions in the body. It contributes to contractility of duodenum, ileum and cecum. In the lungs, it can cause chloride secretion and bronchoconstriction. It can cause smooth muscle contraction in the uterus, bladder and vas deferens. It contributes to rheumatoid arthritis, inflammation, pain sensation and hyperalgesia. It also induces cell proliferation, collagen synthesis, and release of nitric oxide, prostacyclin, TNF-a and interleukins. It can also cause release of glutamate by nerve cells. Glutamate has a variety of actions in the body and excessive release can cause epileptic seizures, ALS, lathyrism, autism and stroke.

Bradykinin acts on the endothelium, the cells that line the inner surface of blood and lymphatic vessels, to cause the blood vessels to dilate. This decreases blood pressure. It also regulates sodium excretion from the kidneys, which can further decrease blood pressure. Kininogen levels are reduced in hypertensive patients. Kinins, including bradykinin, oppose the action of angiotensin II, a hypertensive agent.

So how are mast cells related to this system? A couple of ways. The first way is that they release kininogenases and bradykinin. Tryptase can actually behave as a kininogenase. The second way is by being the exclusive producers of heparin.

As I mentioned above, Factor XII needs to change to Factor XIIa to initiate the formation of bradykinin. It does this when it contacts a negatively charged surface. In the lab, you can use a surface like glass for this. But in the body, it often happens on the surfaces of large, negatively charged proteins like heparin. (Side note: Factor XII is part of the clotting cascade. It can be activated by medical devices like PICC lines and that is why they carry a risk of clot formation.) So by releasing heparin, mast cells cause the formation of bradykinin. When the mast cells release heparin in inappropriate amounts, too much bradykinin is formed.

Overproduction of bradykinin is one of the principal causes of angioedema. In hereditary angioedema, the body is deficient in a component that regulates bradykinin. One of the reasons that physical trauma can cause mast cell degranulation is because it causes formation of bradykinin. Bradykinin in turn causes mast cell degranulation with release of histamine and serotonin, among other contents.

Bradykinin antagonists are being researched as possible therapies for hereditary angioedema. Icatibant is one such medication. Bromelain, found in the stems and leaves of pineapples, are known to suppress swelling caused by bradykinin. Aloe and polyphenols, like those in green tea, are also known to suppress bradykinin activity.

References:

Kaplan AP, Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol. 2010 Aug; 47(13):2161-9

Oschatz C, et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011 Feb 25; 34(2):258-68.

 

Brunnée T, et al. Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions. Clin Exp Allergy. 1997 Jun;27(6):653-63.