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.

 

Chronic urticaria and angioedema: Part 2

CU lesions are swollen pink or red wheals, of variable size, often with surrounding redness. They are generally itchy rather than painful or burning. Angioedema is not itchy, brawny, of a non-pitting quality with indistinct margins and without redness.

There are a number of chronic urticaria and angioedema (CU) subsets that are triggered by environmental sources. These are called physical urticarias.

In aquagenic urticaria, patients develop hives after contact between water and the skin. Temperature is not a factor in this type of urticaria. The hives are generally “pinpoint”, measuring 1-3mm. This is confirmed by applying a water compress at near body temperature to the skin of the upper body for 30 minutes.

Cholinergic urticaria also causes pinpoint hives, but these hives are surrounded by large flare reactions as a result of increased body temperature. Exercise, sweating, emotional stress, hot baths and showers are all frequent triggers of this subtype. Cholinergic urticaria can be benign or life threatening. Testing involves exercise or hot water immersion as these activities raise the core body temperature.

Cold urticaria results in hiving when the skin is exposed to a cold source. Patients may have systemic reactions in the event of full body exposure to the cold (swimming in cold water, etc). This is tested by placing an ice cube on the patient’s skin and waiting for a reaction, which occurs when the skin starts to warm.

Delayed pressure urticaria/angioedema presents as swelling, which may be painful, after the skin is exposed to pressure. While 4-6 hours is a more typical duration for symptoms to present, in some patients it can take 12-24 hours. Working with tools, sitting on a bench, wearing tight clothing, and carrying a heavy purse are all representative triggers. Testing for this subtype involves placing a 15 lb weight on the patient’s shoulder for 10-15 minutes, then waiting for response. Angioedema at the site that evolves following this test is considered a positive test, regardless of whether or not weals are present. This type can be difficult to treat.

Dermatographia is the most common type of physical urticaria. 2-5% of the general population have dermatographia.   Stroking the skin firmly causes a weal and flare reaction where the skin was touched. It does not usually require treatment.

Exercise induced anaphylaxis has two types: those in whom anaphylaxis in provoked strictly by exercise, and those in whom anaphylaxis is triggered when a specific food is consumed prior to exercise. Cholinergic urticaria can also be triggered by exercise, so it is important to distinguish between the two. Exercise anaphylaxis can only be triggered by exercise, whereas cholinergic urticaria results if the patient becomes too hot. People with exercise induced anaphylaxis need to carry epipens and must not exercise alone as reactions can be severe.

Solar urticaria is the development of hives when the skin is exposed to sunlight, generally within minutes. Solar urticarial is further divided in subtypes based upon which wavelengths of light are triggering to the patient. Testing involves lightbox exposure to isolated wavelengths of light. It is distinct from polymorphous light eruption, in which onset is often delayed and can last for days. It can cause papules, papulovesicles and plaque manifestations on the skin.

Recall urticaria is hiving at the site of a previous sting or injection when exposed again to the same trigger.

Vibratory angioedema causes itching and swelling when the skin is exposed to a vibration source. This specific type can show a familial trait. It is confirmed by showing a response after use of a vortex mixer (a piece of lab equipment that mixes solutions in tubes).

 

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.

Chronic urticaria and angioedema: Part 1

Urticaria is the medical term for what we commonly call hives. It is often caused by an allergic process, but can occur for other reasons. Angioedema is swelling affecting the dermis, subcutaneous tissue, mucosa and submucosal tissues. Angioedema can be dangerous, particularly when the airway is obstructed by swelling.

Notably, the two conditions are closely related and are distinguished by the tissues affected. Urticaria is affects only the upper dermis. In this way, angioedema is sometimes considered a form of “inside hives”. These symptoms can occur as a result of allergy but also occur for other reasons.

Urticaria and angioedema are considered acute if they last for less than six weeks and chronic if they last for six weeks or more. Acute urticaria and angioedema are most often, but not always, the result of mast cell and basophil activation by both IgE and non-IgE mechanisms. Activation by complement fragments, antibody binding complexes, cytokines and blood pressure changes can contribute. Importantly, acute urticaria and angioedema usually have an obvious trigger and resolve on their own. Antihistamines and brief courses of steroids are generally used to manage symptoms.

Chronic urticaria usually does not an identifiable cause. The duration of CU (chronic urticaria and angioedema) varies, but physical urticarias are more likely to be long lasting. It is thought that CU affects 0.5-5% of the population. CU patients can have urticaria and angioedema, either alone or together. In these patients, cutaneous mast cells are the driving force and histamine is the most important mediator in these processes.

When biopsied, CU lesions often reveal infiltrates of lymphocytes, but sometimes other cells are present in infiltrates. In CU patients, the clotting cascade is sometimes activated, resulting in increased prothrombin fragments F1 and 2, and D-dimer. These have been suggested as markers of CU, but have not been verified.

CU is only rarely an IgE mediated reaction and is instead associated with a number of chronic conditions. Chronic infections like hepatitis B and C, EBV, HSV, helminthic parasites and H. pylori have been found to cause CU. Complement deficiencies, cryoglobulinemia, serum sickness, connective tissue disease, lupus, rheumatoid arthritis, thyroid disease (both hypo- and hyper-), neoplasms (such as SM), endocrine disorders and use of oral contraceptives are all linked to CU.

Autoimmune diseases are so frequently associated with CU that these patients are subclassified as having autoantibody associated urticaria. Autoantibody associated urticaria and angioedema, linked to thyroid antibodies, anti-IgE antibodies and anti-IgE receptor antibodies, is a subset of chronic idiopathic urticaria. Lupus, dermatomyositis, polymyositis, Sjogren’s and Still’s disease are all associated with CU. Celiac disease has been linked as well.

30-50% of CU patients make IgG antibodies to the IgE receptor and 5-10% make IgG to the IgE molecule. This often does not correlate with skin tests with the patient’s own serum or plasma (ASST, APST) and these tests are not known to affect treatment or identify a specific subgroup of patients. The importance of these IgG antibodies is not clear. Some consider these patients to be more severe, but it is not yet fully understood.

 

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.

Third spacing

The human body essentially keeps fluids in two spaces called compartments.  The first compartment is inside of cells.  This is called intracellular fluid.  It holds about 60% of the body’s fluids.  The second compartment is outside of the cells in the extracellular fluid, which holds about 40% of the body’s fluids.  This second compartment includes spaces like the interstitial compartment and the intravascular compartment.  The interstitial compartment is the fluid that surrounds the cells in tissues.  The intravascular component is mostly blood. 

Third spacing is when body fluids collect somewhere that is not in one of the two compartments where your body can use it.  When fluids are inside cells, your body can use it for chemical reactions.  When fluids are in the interstitial and intravascular compartments, your body can use it for lubrication, chemical reactions and moving chemicals from one place to another.  Fluid in third spaces is outside of the circulatory system and cannot be used by the body.
A common third space is in the abdominal cavity.  When fluid becomes trapped between the tissues and organs of the abdomen, it is called “ascites.”  When fluid accumulates in the interstitial area around the lungs, it is called “pulmonary edema.”  When fluid is found between the layers of the skin or mucous membranes, it is called “angioedema.”
Third spacing is a problem for multiple reasons.  The first is that it compresses the structures around the fluid, like when angioedema puts pressure on the throat and makes it difficult to breathe.  The fluid sometimes affects organ function.  Another reason third spacing is problematic is because it can cause the fluid level in the circulatory system to drop.  This means the amount of blood moving through the body is less than it should be, which decreases blood pressure and increases heart rate.  This can be very dangerous.  If there is not enough blood for the heart to pump, it will stop pumping.
People with a lot of third spacing often have symptoms of dehydration.  This includes things like excessive thirst, fatigue, and reduced urine output. 
Third spacing occurs as a result of anaphylaxis.  It is also a common problem for people with mast cell disease in the absence of anaphylaxis due to “leaking” of chemicals like histamine that push fluid out of the blood vessels and into the tissues.  Fluid replacement is very important to staying stable.
There is a lot of anecdotal information that suggests that IV fluids are helpful to counteracting third spacing in people with mast cell disease.  I get 2L of fluids overnight three times a week, and it has helped immensely.  For me, the IV fluids have stabilized my blood pressure, decreased my heart rate and keep my GI tract moving.  My abdominal pain has improved significantly since starting the IV fluids. My energy is better.  I don’t think that it has been formally written up in article form, but this is a treatment that is quickly gaining momentum in the mast cell community.