Mast cells in the GI tract: How many is too many? (Part seven)

The 2014 Doyle paper provides mast cell counts in colon biopsies for healthy controls, MCAS, and IBS. Mast cells were identified using antibodies for tryptase, CD117, CD25 and CD30 (IHC). Mast cells were counted in both one HPF in the densest portion of the slide and in five HPF and averaged.  In the densest portion of the slide, mast cell counts were higher in 1 HPF than in the average of 5 HPF.  Differences in methodology such as this can contribute to lack of consensus on what constitutes too many mast cells. See Table 21 for details.

Table 21: Comparison of mast cell count in 1 HPF and in the average of 5 HPF
Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.
Microscopy method: 400x magnification, mast cells counted in 1 hpf
Visualization: IHC for tryptase, CD117, CD25 and CD30
HPF Control group A:

Healthy controls

Control group B:

MCAS

Control group C:

IBS

Average Range Average Range Average Range
Average of 5 hpf 19 mast cells/hpf 7-39 mast cells/hpf 20 mast cells/hpf 12-31 mast cells/hpf 23 mast cells/hpf 9-45 mast cells/hpf
1 hpf 26 mast cells/hpf 11-55 mast cells/hpf 28 mast cells/hpf 14-48 mast cells/hpf 30 mast cells/hpf 13-59 mast cells/hpf

 

Other papers also investigated factors that could contribute to differences in mast cell counts. The 2015 Sethi paper evaluated differences in GI mast cell counts between men and women.  Women had  marginally higher counts in both IBS and control groups. See Table 22 for details.

Table 22: Difference in mast cell count between men and women with chronic diarrhea and asymptomatic controls
Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: CD117 (IHC)
Sample type Study group: Women Study group: Men Control group: Women Control group: Men
Colon Average Range Average Range Average Range Average Range
30 mast cells/hpf 27-34 mast cells/hpf 27 mast cells/hpf 24-31 mast cells/hpf 24 mast cells/hpf 22-37 mast cells/hpf 21 mast cells/hpf 19-24 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

One paper looked at the difference in mast cell count in the rectum of healthy patients over the age of 55 and under.  Please note that these counts were made using a much lower magnification than other papers in this series, so mast cell counts are not directly comparable. Mast cells were identified using antibodies to tryptase (IHC). See Table 23 for details.

Table 23: Differences in GI mast cell count in healthy patients over and under 55 years of age.
Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.
SPECIAL NOTE: THESE COUNTS WERE MADE AT HALF THE MAGNIFICATION OF OTHER PAPERS IN THIS SERIES.  THESE MAST CELL COUNTS ARE NOT DIRECTLY COMPARABLE TO OTHER STUDIES.
200x magnification, number of hpf not explicitly stated, assumed mast cells counted in 1 hpf
Visualization: Tryptase (IHC)
Sample type Study group: Healthy, over 55 years old Study group: Healthy, under 55 years old Control group B:

No control group

Rectum Average Range Average Range Average Range
40.5 ± 2.4 mast cells/hpf 51.7 ± 4.1 mast cells/hpf N/A N/A

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

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

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

Mast cells in the GI tract: How many is too many? (Part Five)

One of the most interesting papers on mast cell burden in the GI tract evaluates patients with chronic urticaria.  The patients in this study did not have GI symptoms, but they did have skin symptoms related to consumption of trigger foods.  Mast cells were identified using antibodies to CD117 and tryptase, and were counted in five hpf and averaged.  The healthy controls for this study were from two countries in order to evaluate the effect of diet on mast cell count in healthy patients.  There was no difference between the control groups from different countries.

The control group as a whole averaged 20.2 mast cells/hpf in the stomach.  The chronic urticaria group as a whole averaged 32.4/hpf in the stomach.  This paper also assessed the mast cell count in chronic urticaria patients whose biopsies did not display any tissue damage.  In this group, mast cell count averaged 30.4/hpf. In all instances, cells were scattered and not clustered.  Mast cell count in CU patients were 61% increased compared to controls. See Table 15 for details.

In the duodenum (small intestine), the healthy control group averaged 32.5 mast cells/hpf.  The chronic urticaria group had 44.8/hpf and chronic urticaria patients with normal biopsies (not tissue damage) averaged 45.2/hpf.  Again, cells were scattered and not clustered. Mast cell count in CU patients were 37.8% increased compared to controls. See Table 16 for details.

The implication here is that even in the absence of GI symptoms, activation of mast cells in the GI tract might release enough histamine to cause urticaria.  An important feature of this paper is that it discusses “pseudoallergens”, which it describes as “non-specific histamine-release” substances. Fourteen of the patients in this study had a history of “pseudoallergen” food triggers that irritated their urticaria. In these patients, mast cell count was actually lower in the stomach than those who didn’t have food “pseudoallergen.” See quote below.

“The skin lesions of CU are caused by vasoactive mediators released through specific or non-specific mast cell degranulation in the skin or elsewhere. CU patients are particularly susceptible to the non-specific histamine-releasing effect of pseudoallergenic substances in various foods and drugs, and the success rate of pseudoallergen-free diets varies between 30 and 50%.  It is conceivable that food pseudoallergens induce non-specific mast cell degranulation, rather in the gastrointestinal tract than elsewhere. Activation of many intestinal mast cells may then result in enough histamine release to cause urticaria either directly or indirectly.” (Minnei 2006)

 

Table 15: Mast cell count in stomach of patients with chronic urticaria
Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.
Microscopy method: 400x magnification, counted in 5 hpf and averaged
Visualization: CD117 and tryptase
Sample type Study group: Chronic urticaria Study group: Chronic urticaria, biopsies normal Control group A:

Healthy controls

Stomach Average Range Average Stomach Average Range
32.4 mast cells/hpf 29.5-35.4 mast cells/hpf 30.4 mast cells/hpf 26.2-34.6 mast cells/hpf 20.2 mast cells/hpf 17.4-22.9 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 16: Mast cell count in small intestine (duodenum) of patients with chronic urticaria
Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.
Microscopy method: 400x magnification, counted in 5 hpf and averaged
Visualization: CD117 and tryptase
Sample type Study group: Chronic urticaria Study group: Chronic urticaria, biopsies normal Control group A:

Healthy controls

Duodenum Average Range Average Stomach Average Range
44.8 mast cells/hpf 39.2-50.3 mast cells/hpf 45.2 mast cells/hpf 38.4-52.1 mast cells/hpf 32.5 mast cells/hpf 29.4-35.6 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

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

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

Chronic urticaria and angioedema: Part 5

Chronic urticaria has a very well described stepwise treatment standard, which I will describe briefly here. If resolution is not achieved with the method described in one step, the next step is executed.

  • A second generation H1 antihistamine like cetirizine is begun with standard daily dosing. Triggers should be avoided wherever possible.
  • Dosage of second generation H1 antihistamine is increased.
  • Another second generation H1 antihistamine is added to the regimen. (For example, cetirizine and fexofenadine taken together).
  • An H2 antihistamine is added. About 15% of histamine receptors in the skin are H2, so some patients see benefit from this.
  • A leukotriene receptor antagonist like montelukast is added.
  • A first generation H1 antihistamine like diphenhydramine is added at bedtime.
  • A strong antihistamine like hydroxyzine or doxepin is added and dosages increased accordingly.
  • If all else has failed, consider addition of medications like Xolair, cyclosporine, or other immunosuppressants.

Treatment of angioedema is dependent upon the cause of the angioedema (C1 esterase deficiency, ACE inhibitor, etc). However, it is generally agreed upon that upper airway swelling, even if mild, should be treated aggressively. Intramuscular epinephrine is indicated for this situation, with advisories in numerous papers to administer epinephrine as early as possible if airway swelling is present.

Reactions caused by IgE are the most likely to respond immediately to epinephrine. Hereditary and acquired angioedema are less likely to respond to epinephrine. If the patient is on beta blockers, glucagon is the drug of choice, as beta blockers interfere with action of epinephrine.

I am doing a detailed follow up post on treatment options for the various types of angioedema.

 

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 Med 2007; 8:72-80.

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.