The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 57

71. What other diseases “look like” mast cell disease?

Mast cell diseases have many symptoms that are also commonly found in other disorders. This is one of the reasons why it is difficult to diagnose correctly. The following conditions have symptoms that can look like mast cell disease.

Neuroendocrine cells are specialized cells that help to pass signals from the nervous system to nearby cells, causing those cells to release hormones. There are many types of neuroendocrine tumors. Some conditions that look like mast cell disease are caused by these tumors. Symptoms from them are caused by the response of too much hormone.

Carcinoid syndrome is the result of a rare cancerous growth called carcinoid tumor. This tumor releases too much serotonin into the body. This can cause flushing, nausea, vomiting, diarrhea, difficulty breathing, and cardiovascular abnormalities such as abnormal heart rhythm. Mast cells also release serotonin but they release much less than carcinoid tumors.

VIPoma means vasoactive intestinal peptide –oma. When a word has –oma at the end, it means that it is a tumor. A VIPoma is a tumor that starts in the pancreas. It releases a chemical called vasoactive intestinal peptide. VIPoma can cause flushing, low blood pressure, and severe diarrhea leading to dehydration. A VIPoma can also abnormalities in the composition of the blood. Many patients have low potassium, high calcium, and high blood sugar.

Pheochromocytomas start as cells in the adrenal glands. They release excessive norepinephrine and epinephrine. They can cause headaches, heart palpitations, anxiety, and blood pressure abnormalities, among other things.

Zollinger-Ellison syndrome is a condition in which tumors release too much of a hormone called gastrin into the GI tract. This causes the stomach to make too much acid, damaging the stomach and affecting absorption.

Some blood cancers can cause mast cells to become overly activated. They may also cause an increase in tryptase, an important marker in diagnosing systemic mastocytosis.

Some other cancerous tumors like medullary thyroid carcinoma can cause mast cell type symptoms including flushing, diarrhea, and itching.

Most diseases with any allergic component can look like mast cell disease.

Eosinophilic gastrointestinal disease occurs when certain white blood cells called eosinophils become too reactive, causing inflammation to many triggers. Furthermore, people are more frequently being diagnosed with both EGID and mast cell disease.

Celiac disease is an autoimmune disease in which gluten causes an inflammatory reaction inside the body. The damage to the GI tract can be significant. Malabsorption is not unusual. Children with celiac disease may grow poorly. Bloating, diarrhea, ulceration, and abdominal pain are commonly reported.

FPIES (food protein induced enterocolitis syndrome) can cause episodes of vomiting, acidosis, low blood pressure and shock as a result of ingesting a food trigger.

Traditional (IgE) allergies can also look just like mast cell disease. They are usually distinguished by the fact that mast cell patients may react to a trigger whether or not their body specifically recognizes it as an allergen (does not make an IgE molecule to the trigger). Confusingly, it is possible to have both traditional IgE allergies and mast cell disease.

Postural orthostatic tachycardia syndrome (POTS) is commonly found in patients with mast cell disease. However, POTS itself can have similar symptoms to mast cell disease. Palpitations, blood pressure abnormalities, sweating, anxiety, nausea, and headaches are some symptoms both POTS and mast cell disease have. There are also other forms of dysautonomia which mimic the presentation of mast cell disease.

Achlorhydria is a condition in which the stomach does not produce enough acid to break down food properly. This can cause a lot of GI pain, malabsorption, anemia, and weight loss.

Hereditary angioedema and acquired angioedema are conditions that cause a person to swell, often severely. Swelling may affect the airway and can be fatal if the airway is not protected. Swelling within the abdomen can cause significant pain and GI symptoms like nausea and vomiting.

Gastroparesis is paralysis of the stomach. People with GP often experience serious GI pain, vomiting, nausea, diarrhea or constipation, bloating and swelling.

Inflammatory bowel diseases and irritable bowel syndrome can all cause GI symptoms identical to what mast cell patients experience.

This list is not exhaustive. There are many other diseases that can look similar to mast cell disease. These are the ones I have come across most commonly.

For more detailed reading, please visit the following posts:

Gastroparesis: Part 1
Gastroparesis: Treatment (part 2)
Gastroparesis: Diabetes and gastroparesis (Part 3)
Gastroparesis: Post-surgical gastroparesis (Part 4)
Gastroparesis: Less common causes (Part 5)
Gastroparesis: Autonomic nervous system and vagus nerve (Part 6)
Gastroparesis: Idiopathic gastroparesis (Part 7)

Food allergy series: Food related allergic disorders
Food allergy series: FPIES (part 1)
Food allergy series: FPIES (part 2)
Food allergy series: Eosinophilic colitis
Food allergy series: Eosinophilic gastrointestinal disease (part 1)
Food allergy series: Eosinophilic gastrointestinal disease (part 2)
Food allergy series: Eosinophilic gastrointestinal disease (part 3)
Food allergy series: Eosinophilic esophagitis (Part 1)
Food allergy series: Eosinophilic esophagitis (Part 2)
Food allergy series: Eosinophilic esophagitis (Part 3)

Angioedema: Part 1
Angioedema: Part 2
Angioedema: Part 3
Angioedema: Part 4

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 5
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 6
Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 7

Take home points: September 2015

Naturally occurring mast cell stabilizers: Part 1

Naturally occurring mast cell stabilizers: Part 2

Naturally occurring mast cell stabilizers: Part 3

Naturally occurring mast cell stabilizers: Part 4

Amentoflavone Ginkgo biloba, St. John’s Wort Decreases histamine release
Artekeiskeanol A Artemisa keiskeana May treat arthritis

Decreases mast cell degranulation

Decreases production of IL-13 and TNF

Curcimin Turmeric Decreases degranulation

Decreases production of IL-4 and TNF

Ellagic acid Strawberries, raspberries, pomegranate, walnuts Suppresses IgE activation

Decreases release of histamine, TNF, IL-6

Emodin Rhubarb, frangula bark Decreases IgE degranulation

Decreases IgE triggered production of TNF, PGD2, LTC4

Decreases secretion of TNF and IL-6

Epigallocatechin gallate White and green teas, apples, onions, hazelnuts Decreases degranulation

Decreases LTC4 secretion

Fisetin Apples, onions, persimmon, strawberries, cucumber Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-1b, IL-6, IL-8 and TNF

Decreased action of NF-kB, decreased mediator production

Furanocoumarin from Angelica dahurica Angelica dahurica Inhibits COX-2 and 5-LO, decreasing production of prostaglandins and LTC4
Genistein Genista tinctoria Decreases IgE degranulation

Decreases histamine release

Nature tyrosine kinase inhibitor

Ginkgetin Gingko biloba Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes
Gnetin H Paeonia aneomala Resveratrol derived polymer

Decreases mast cell degranulation

Effective at lower dose than reservatrol

Decreases histamine secretion

Decreases production of TNF, IL-4, COX-2 and PGE2

Homoisoflavonone Cremastra appendiculata Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes

Decreases IgE triggered production of TNF and IL-6

Honokiol Magnolia obovata Suppresses allergic response and basophil activation
Hydroxytyrosol Olive oil, olive leaves Inhibited activation of mast cells at high concentration
Hypothemycin Hypomyces mushrooms Interfere with activation of CKIT and IgE receptors, inhibiting mast cell activation

 

Decreases production of IL-4

Kaempferol Potatoes, squash, cucumbers, peaches, Aloe versa Decreases IgE degranulation

Decreased IgE triggered histamine release

Affects estrogen signaling

Luteolin Celery, carrots, chamomile tea Prophylactic use of luteolin suppresses activation of mast cells and T cells

Decreases IgE degranulation

Decreases production of mediators

Magnolol Magnolia obovata Suppresses allergic response and basophil activation
Morin Osage orange, guava Decreases mast cell degranulation

Decreases IgE activation

Myricetin Walnuts, onions, red grapes Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-6 and TNF

Decreased action of NF-kB, decreased mediator production

Polydatin Resveratrol precursor

Makes small intestine mucosa less “leaky” and inhibited allergic reaction in intestines

Decreases degranulation by up to 65%

Decreases histamine in intestinal mucosa and serum

Decreases production of IL-4

Quercetin Red onion, sweet potato, kale Inhibits production of histamine, prostaglandins, leukotrienes, IL-1b, IL-6, IL-8 and TNF
Resveratrol Grapes, raspberries, blueberries, peanuts Directly interferes with degranulation

Decreases production of TNF, IL-6 and IL-8

Rottlerin Mallotus philippensis Decreases degranulation of airway mast cells

Decreases histamine release

Suppresses IgE activation

Rutin Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-1b, IL-6, IL-8 and TNF

Decreased action of NF-kB, decreased mediator production

Scopoletin Stinging nettle, Japanese belladonna, chicory, passion flower Decreases production of TNF, IL-6, IL-8

Inhibits NF-kB, affecting mediator production

Selinidin Angelia keiskei Inhibits IgE degranulation

Decreases production of LTC4 and TNF

Substance Source Function
Thunberginol A Hydrangeae macrophylla Decreases histamine release

Decreases production of TNF and IL-4

Thunberginol B Hydrangeae macrophylla Decreases degranulation from IgE or other sources

Decreases IgE triggered production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF

Xanthones from purple mangosteen Garcinia mangostana Decreases release of histamine, PGD2, LTC4 and IL-6

 

Role of sex hormones in hereditary angioedema

Gastroparesis: Autonomic nervous system and vagus nerve (Part Six)

  • ANS controls many involuntary functions including digestion and therefore gastric emptying
  • The vagus nerve coordinates gastric motility
  • ANS dysfunction inhibits digestion and motility
  • GP is common in patients with ANS conditions, like POTS
  • Treatment of autonomic dysfunction (as in POTS) can sometimes improve GP
  • Damage to the vagus nerve can cause liquids to move rapidly out of the stomach while solids are retained
  • Surgery and high blood sugar can damage the vagus nerve
  • In GP patients, nerve cells are not shaped correctly
  • 83% of GP patients have abnormalities in their stomach biopsies

Gastroparesis: Idiopathic gastroparesis (Part Seven)

  • 35-67% of GP cases are idiopathic (IGP)
  • IGP affects three times more women than men, especially young and middle-aged women
  • IGP is more likely in young women who are overweight or obese
  • Moderate to severe abdominal pain was more frequent in IGP than other types
  • Nausea, abdominal pain, vomiting, bloating and feeling full are common in IGP
  • Medications that may be helpful but need investigation include sildenafil, paroxetine, cisapride, tegaserod, clonidine and buspirone

Role of sex hormones in hereditary angioedema

Sex hormones are well known for influencing symptoms of immune mediated conditions. Estrogen can affect cell proliferation and activation. Menses, pregnancy, menopause, and use of oral contraception are known to affect hereditary angioedema (HAE) but it is not yet clear how.

One hypothesis is that estrogen may activate the kallikrein-kinin system, thereby increasing production of bradykinin. Another hypothesis is that estrogen can affect the expression of the FXII gene, which produces the initiating molecule in the bradykinin pathway. Estrogen may also regulate the B2 receptors that bradykinin binds to. While all of these ideas are possible, there have not yet been any definitive findings.

In female patients, onset of HAE often correlates with the start of puberty. Menses, pregnancy and delivery also correlate with flare ups of HAE. Puberty makes HAE attacks more frequent and severe in 56.7% of cases; menses does the same in 35.3%; ovulation, 14%. Use of estroprogestin contraceptives irritate and worsen HAR in 63-80% of HAE women. The first trimester of pregnancy is known to be a difficult time for HAE women, as circulating estrogen is particularly high and many women discontinue maintenance therapy out of safety concerns for the fetus.

In patients with type III HAE in whom a Factor XII mutation has been identified, episodes occur almost exclusively during periods of high estrogen. This initial observation led to type III to be called “estrogen dependent HAE”, but this only refers to a subset of patients and has fallen out of use. Estrogen levels do not affect symptoms in other type III HAE patients (without the Factor XII mutation) and in many acquired angioedema patients.

Female HAE patients of reproductive age, who are not using oral contraceptives, often have polycystic or multifollicular ovaries. Ovulation is a complex multistep process in which two steps are controlled by C1INH.

 

 

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

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

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

 

 

 

 

Angioedema: Part 4

Deficiencies of an early component of the classical complement pathway (C1q, C1r, C1s, C2, C4) have been associated with lupus like autoimmune conditions. The reason for this is that these proteins help to clean up large groups of molecules called immune complexes before they can cause inflammation. Dead cells are also removed by these complement molecules. Without these proteins, immune complexes and dead cells are not removed and cause local irritation.

In HAE types I and II, complement proteins C2 and C4 are low. However, HAE patients have been shown to have a normal level of immune complexes. For this reason, it is still unclear whether or not low C2 and C4 may contribute to overall inflammation and pain profile for these patients. Despite this fact, it is still possible that deficiency in C2 and C4 may predispose HAE patients to autoimmune diseases.

A number of studies have assessed the prevalence of autoimmune conditions in HAE patients. One study looked specifically for two thyroid antibodies and found that 13.2% HAE patients had autoantibodies to the thyroid.

When expanding the autoimmune profile to include “lupus-like” conditions such as those often associated with complement deficiencies, a much higher prevalence of autoantibodies was found in HAE patients. Three other studies measured the frequency of ANA (anti-nuclear antibody, a generic marker found in many autoimmune conditions); RF (Rheumatoid Factor, associated with rheumatoid arthritis); anti-thyroglobulin(autoimmune thyroiditis); TPO (thyroid peroxidase, autoimmune thyroiditis); and thyroid antibodies along with some or all of the following antibodies: anti-dsDNA (anti double stranded DNA, systemic lupus erythematosus); ENA (extractable nuclear antigens, a panel of six tests that can identify mixed connective tissue disease, systemic lupus erythematosus, Sjogren’s, Scleroderma and dermatomyositis); TMA (microsomal antibodies, autoimmune thyroiditis); AMA (antimitochondrial antibodies, drug-induced or systemic lupus erythematosus, Sjogren’s, autoimmune hemolytic anemia, autoimmune liver disease); ANCA (antineutrophil cytoplasmic antibodies); anti-cardiolipin (systemic lupus erythematosus, Behcet’s, antiphospholipid syndrome); anti-b2GPI (b2-glycoprotein I, systemic lupus erythematosus, Behcet’s, antiphospholipid syndrome); anti-C1q (urticarial vasculitis); anti-P ribosomal (systemic lupus erythmatosis); EMA (anti-endomysial antibodies, Celiac disease); tTG (anti-tissue transglutaminase antibodies, dermatitis herpetiformis); and ASCA (anti-saccharomyces cerevisiae antibodies, Behcet’s, Celiac disease, Crohn’s disease, ulcerative colitis). The three studies found that 47.5-48% HAE patients had at least one of these autoantibodies. In comparison, the average for healthy controls was 10%.

Other studies looked at prevalence of autoimmune disease rather than autoantibodies. One study found that 12% of HAE patients had at one of the following autoimmune conditions: glomerulonephritis, Sjogren’s syndrome, irritable bowel disease, thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, drug induced lupus, pernicious anemia, juvenile RA with IgA deficiency, or sicca syndrome.

Other studies found that 3.4% HAE patients had lupus rash or glomerulonephritis; that 0.9% had RA or Sjogren’s; that 11.5% had Crohn’s, Celiac, Hashimoto’s thyroiditis, discoid lupus erythematosus, chronic lymphocytic leukemia, MGUS, or IgA deficiency; that 11.4% had systemic lupus erythematosus, Celiac, multiple sclerosis-like syndrome, systemic sclerosis, or mixed connective tissue disease; that 4.2% had lupus like syndrome, psoriatic arthritis, mixed connective tissue disease or antiphospholipid syndrome; that 0.4-0.9% had lupus-like or unspecific cutaneous lupus or subacute lupus.

An interesting feature of HAE is the frequent complaint of decreased sense of smell. Facial edema and chronic rhinosinusitis were not found to be the cause. However, systemic lupus erythematosus and Sjogren’s syndrome can also cause impairment of smell. Despite the frequency of lupus in HAE patients, it usually affected the mucocutaneous regions of the body and was generally mild.

In addition to the frequent prevalence of autoantibodies and autoimmune disease, HAE patients have increased B cell activation and autoreactive B cells. This can also contribute to an inflammatory and autoimmune profile.

 

References:

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

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

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.

Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).

 

 

 

 

Angioedema: Part 3

Acquired angioedema (AAE) is characterized by a deficiency of C1INH not associated with a genetic defect; overactivation of the classical complement pathway; and frequent angioedema episodes. AAE is rare, about ten times less common than HAE. However, the two conditions are clinically identical. AAE often presents with low CH50, C2, C4 and sometimes C1q, with low or poorly functioning C1INH.

AAE was originally associated with lymphoma and has since been found secondary to a number of autoimmune and hematologic diseases, particularly lymphoproliferative conditions and monoclonal gammopathy of unknown significance (MGUS, which often precedes multiple myeloma). Historically, AAE has been divided into two groups: type I, which I just described; and type II, in which there are IgG antibodies to C1INH that inactivate C1INH. However, further research found that anti-C1INH antibodies are also found in type I. It has since been recognized that these are really different presentations of the same condition, with lymphoma cells depleting C1INH more readily. There have been documented instances in which achieving remission from lymphoma cured the associated AAE.

There are other types of angioedema that are difficult to classify. Idiopathic angioedema is the instance of three episodes in 6-12 months without a clear trigger or pathology. It is distinguished from hereditary angioedema by the shorter duration of symptoms. Further testing demonstrates normal levels and function of C1INH in these patients. This is sometimes called “idiopathic non-histaminergic AAE” to distinguish from an allergic process.

Type III HAE patients are sometimes positive for mutations in the Factor XII gene. However, in some patients, no mutation is found. All type III patients demonstrate normal level and function of C1INH. Type III patients experienced four attacks per year on average, with 42.9% having swelling in the airway. 85% had abdominal attacks, with some severe enough to result in emergency (though unnecessary) surgical procedures and ascites, free fluid in the abdomen.

In the patients with the Factor XII mutation, attacks were most likely to occur during high estrogen states, but were not exclusive to these periods. Initial attacks for this patient group usually occurred while on oral contraceptives or during pregnancy. However, men and children were also found to have Factor XII mutations. Initial attacks were less likely to affected by estrogen state in type III HAE with no FXII mutation or in idiopathic non-histaminergic angioedema. .

23% of type III patients exhibited elevated D-dimer levels outside of attack periods. Some also had extended clotting times. In the FXII mutated group, bruising was seen in a number of patients when swelling in the swollen portions of anatomy, but strictly in the skin. 27.9% of pregnancies in this group terminated in spontaneous miscarriage. Two births were extremely premature and one liveborn child died shortly after birth with no obvious cause of death.

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

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

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

Kajdacsi, E., et al. Endothelial cell activation during edematous attacks of hereditary angioedema types I and II. J Allergy Clin Immunol 133 (6); 1686-1691.

Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).

Madsen, Daniel Elenius, et al. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: implication for a role in hereditary angioedema. Biochimica and Biophysica Act 1850 (2015) 1336-1342.

Lasek-Bal, Anetta, et al. Hereditary angioedema with dominant cerebral symptoms finally leading to chronic disability. Clinical Neurology and Neurosurgery 135 (2015) 38-40.

 

 

 

Angioedema: Part 2

Patients with HAE may have normal bloodwork for routine tests. Blood counts, electrolytes and liver function tests are often unremarkable. Upon further testing, complement protein C4 is often low. This deficiency is most profound during attacks but often continues in interim periods. C3 is usually normal.

  • In HAE type I, C1 inhibitor (C1INH), C4 and C2 levels are low, while C1q is normal.
  • In HAE type II, C1INH is normal or marginally increased, C4 and C2 levels are low, and C1q is normal. C1INH functional tests yield low function.
  • In HAE type III, CIINH is normal and functions normally and C4 is sometimes normal. Mutation for Factor XII is sometimes found. This is still largely a diagnosis of exclusion based upon similar clinical presentation as the other two types.

Hereditary angioedema (HAE) attacks carry the risk of significant danger as airway constriction can lead to suffocation. More than half of HAE patients will experience laryngeal swelling at least once in their lifetime. Swells typically last 2-3 days and then resolve over the following two days. Antihistamines and steroids are ineffective in mitigating swelling of this type.

HAE attacks have many triggers in the same way mast cell disease does. HAE was originally termed angioneurotic disease because patients frequently had a strong emotional event that activated the disease. In women, swells may correspond to changes in circulatory estrogen – pregnancy, menopause, puberty, menses. Psychological stress is a well characterized trigger for HAE and patients are strongly urged to eliminate sources of stress wherever possible. ACE inhibitors are known to interfere with regulation of the pathway to produce bradykinin and should therefore by avoided.

The last few years have seen several medications for acute angioedema attacks come to market. Cinryze, Berinert and Ruconest are C1INH solutions for intravenous infusion that can be administered at home. Kalbitor is a kallikrein inhibitor that is formulated for subcutaneous injection. Firazyr blocks the bradykinin receptor and is also available for injection. It is universally agreed that these medications should be available on demand in the event of a swell as they have been shown to safely and effectively reduce the risk to life.

With the advent of these targeted medications, more outmoded treatments are start to be phased out. Previous treatment modalities include fresh frozen plasma for acute attacks or short term prophylaxis, anabolic steroids like anabolic steroids, such as danazol, and antifibrinolytic medications, such as tranexamic acid. These medications often had difficult side effects, but still see some use for prophylaxis to avoid swell episodes. For short term prophylaxis for procedures, 1000-2000U of C1INH, 2U of freshly frozen plasma or a week of high dose danazol can be used.

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

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

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

Kajdacsi, E., et al. Endothelial cell activation during edematous attacks of hereditary angioedema types I and II. J Allergy Clin Immunol 133 (6); 1686-1691.

Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).

Madsen, Daniel Elenius, et al. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: implication for a role in hereditary angioedema. Biochimica and Biophysica Act 1850 (2015) 1336-1342.

Lasek-Bal, Anetta, et al. Hereditary angioedema with dominant cerebral symptoms finally leading to chronic disability. Clinical Neurology and Neurosurgery 135 (2015) 38-40.

 

 

 

Angioedema: Part 1

Hereditary angioedema (HAE) is a heritable blood disorder that causes episodes of protracted swelling, which can be life threatening. It has three subtypes, with two known to be caused by a mutation in the C1-INH (C1 inhibitor) gene.

HAE causes angioedema, a condition in which fluid leaves the bloodstream and passes into the space between the deep dermis and subcutaneous tissue. Swelling episodes can last for up to five days and swelling resolves between attacks. About 30% of HAE patients also have a rash similar to erythema marginatum, pink, slightly raised rings that don’t itch or wheal. HAE patients do not have hives or itching, an important distinction that allows diagnostic separation from chronic urticaria and angioedema

Swelling can occur in any region of the body, but face, GI tract, limbs, penis and scrotum are the most common. Angioedema of the tongue and pharynx can compromise the airway, as can edema of the larynx. In these patients, a tracheostomy may need to be placed.

Over 90% of patients suffer severe abdominal swells lasting 2-4 days. Abdominal pain, nausea, vomiting and diarrhea are common symptoms in this group. It is not unusual for doctors to assess the patient as having an “acute abdomen” in need of surgical intervention. Likewise, unnecessary surgery is often performed looking for the source of the swelling. These symptoms occur as a result of edema in the bowel wall, with complete or partial obstruction, sometimes causing ascites, or free fluid in the abdomen.

Angioedema seen in HAE patients is caused by excessive production of bradykinin, which is initiated by factor XII (also called Hageman factor). There are three types of HAE:

  • Patients with HAE type I (85% of cases) have too little C1 inhibitor which functions poorly.
  • Patients with type II (15% of cases) have normal levels of C1 inhibitor but it does not function correctly.
  • Patients with HAE type III have normal levels and function of C1 inhibitor, but have symptoms and treatment responses similar to those with types I and II. Current research indicates that these people sometimes have mutations in the gene for Factor XII, which is also involved in the production of bradykinin.

Bradykinin acts on B2 receptors to cause blood vessels to dilate, decreasing blood pressure. It also increases vessel permeability, allowing fluid and cells to leave the blood stream and become trapped in tissues, resulting in angioedema.

C1 inhibitor (C1INH) is a molecule with multiple regulatory functions. Its name derives from its relation to the complement protein C1, the activation of which is the initiating step in the classical pathway for the complement system, a mechanism for fighting infections. A side product of this pathway is the large scale production of complement proteins C3a and C5a, both of which can induce anaphylaxis. C1INH also regulates steps involving the formation of plasminogen and plasmin, which prevent the formation of blood clots.

C1INH also inhibits the molecule Factor XII, also called Hageman Factor. C1INH prevents Factor XII from activating itself, the first step in a pathway that produces bradykinin. Activation of Factor XII causes formation of molecules XIIa and XIIf. Factor XIIa induces conversion of prekallikrein to kallikrein, and kallikrein then acts on high molecular weight kininogen to release bradykinin. All of those steps are regulated by C1INH.

 

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

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

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

Kajdacsi, E., et al. Endothelial cell activation during edematous attacks of hereditary angioedema types I and II. J Allergy Clin Immunol 133 (6); 1686-1691.

Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).

Madsen, Daniel Elenius, et al. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: implication for a role in hereditary angioedema. Biochimica and Biophysica Act 1850 (2015) 1336-1342.

Lasek-Bal, Anetta, et al. Hereditary angioedema with dominant cerebral symptoms finally leading to chronic disability. Clinical Neurology and Neurosurgery 135 (2015) 38-40.

 

 

 

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.