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

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 21

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

30. Why does my skin get red and itchy?
• Flushing is one of the hallmark signs of mast cell disease. It is sometimes the symptom that drives providers to look at mast cell disease as a potential diagnosis.
• Mast cells make and release many chemicals. These chemicals are commonly called mediators because they mediate many reactions in the body that affect the body in many different ways.
• Some mast cell mediators make blood vessels relax. The vessels get a little wider. When the vessels get bigger, the ones under the skin get closer to the skin. Because those vessels show red from the blood in them, the blood is closer to the skin so the skin looks red.
• Flushing is often asymmetrical. There isn’t a hard and fast reason for why this happens but is likely caused by local mast cell mediator release. Essentially, if the mast cells on the right side of your face get irritated, the right side is more likely to flush than the left side.
Flushing is mostly mediated by prostaglandin D2. Aspirin is often prescribed for mast cell patients that tolerate it because aspirin blocks cells from making prostaglandins. This is because aspirin interferes with the molecule that manufactures them. Many other substances can also interfere with this, including other NSAIDs. Another class of drug, 5-lipoxygenase inhibitors, can also stop production of prostaglandins in a different way.
• To a lesser extent, histamine contributes flushing and antihistamines sometimes help.
What exactly causes itching is still not entirely clear. There are special little places in your body called itch receptors. When they notice something itchy, it’s their job to raise the alarm. We think that mast cells carry the message from those places to the nervous system that then spread the itch signal. It’s like carrying the flame of one candle from the itch receptor to the nervous system, which sets the forest on fire.
• Hydroxyzine and other antihistamines are often used for itching. Corticosteroids like prednisone, either oral or topical, may help. Also, medications that interfere with prostaglandin production, like an NSAID or a 5-lipoxygenase inhibitor, sometimes help.

For more detailed reading, please visit these posts:
The Provider Primer Series: Management of mast cell mediator symptoms and release
Prostaglandins and leukotrienes
Mast cell mediators: Prostaglandin D2 (PGD2)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 20

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

29. Why do I swell up when I have a reaction? Where does the fluid come from and where does it go?
• Your body feeds its cells by keeping blood circulating. The blood passes by cells. The cells pull nutrients, oxygen, and other things they want out of the blood. In return, the cells release their wastes into the bloodstream to carry them away to a place where they can be broken down.
• Mast cells make and release many chemicals. These chemicals are commonly called mediators because they mediate many reactions in the body that affect the body in many different ways.
• Mast cell mediators do many things. They can make blood vessels get looser or tighter to help control heart rate and blood pressure. Their ability to make blood vessels relax is the important point when considering swelling. When mast cells release certain mediators, the vessels relax and get a little wider.
• Vessels are made of a complicated network of cells and fibers. It’s like an afghan blanket: some parts of mostly solid and in other places, there are holes you can put your fingers through. When the vessels relax, those holes get larger so it’s easier for things to fall through the holes. In this case, what falls through the hole is fluid from the blood.
• Keep in mind that blood is a mixture of many things. For right now, let’s divide it into cells and everything else. Everything else is a liquid with some stuff dissolved in it.
• When the blood vessels relax, that liquid from the blood trickles out of the blood vessel and goes into the tissue. In some cases, if the blood vessels relax enough, cells actually fall out of the bloodstream and end up in tissue, too.
• The problem is that once you fall out of the bloodstream, you can’t just turn around and go right back in. That’s why swelling takes longer to subside than other symptoms, even with appropriate treatment.
• Everyone is familiar with the bloodstream. Less familiar is the lymphatic circulatory system. Lymphatic circulation is how your body moves things that fall out of the blood back to the bloodstream. This process is slower than processes that can release other symptoms and can sometimes take days.
• When you swell up, fluid falls out of your bloodstream and gets stuck in your tissues. The cells nearby will absorb some of the fluid and take up molecules they can use. However, if there is a lot of extra fluid there, the cells nearby cannot take up all of the fluid. Gradually, your lymphatic system sucks up that fluid and brings it back toward the heart so it can get back into the bloodstream.
• When you get hives (urticaria), it happens because fluid falls out of the bloodstream in a layer of tissue in the skin called the upper dermis.
• When you get angioedema, it happens because fluid falls out of the bloodstream in lower portions of tissue in the skin called the dermis, subcutaneous tissue, mucosa, and submucosa.
• The fact that the process for hives and angioedema is so similar and really distinguished only by which tissue layer they affect is the reason urticaria and angioedema so commonly occur together and are discussed together.

For more detailed reading, please visit the following posts:
Chronic urticaria and angioedema: Part 1
Chronic urticaria and angioedema: Part 2
Chronic urticaria and angioedema: Part 3
Chronic urticaria and angioedema: Part 4
Chronic urticaria and angioedema: Part 5
The Provider Primer Series: Management of mast cell mediator symptoms and release

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 3

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

6. What symptoms does mast cell disease cause?

  • Mast cell disease can cause just about any symptom. Seriously.
  • Mast cell disease can cause symptoms in every system of the body. This is because mast cells are found in tissues throughout the body. They are intimately involved in lots of normal functions of the human body. When mast cells are not working correctly, lots of normal functions are not carried out correctly. When this happens, it causes symptoms. In short, mast cells can cause symptoms anywhere in the body because they were there already to help your body work right.
  • Skin symptoms can include flushing, rashes, hives (urticaria), itching, blistering, and swelling under the skin (angioedema).
  • GI symptoms include nausea, vomiting, diarrhea, constipation, problems with the GI not moving correctly in general (GI dysmotility), swelling of the GI tract, chest and abdominal pain, belching, bloating, discolored stool, excessive salivation, dry mouth, and trouble swallowing.
  • Cardiovascular symptoms include high or low blood pressure, fast or slow heart rate, irregular heartbeat, and poor circulation.
  • Neuropsychiatric symptoms include brain fog, difficulty concentrating, difficulty sleeping at night, excessive tiredness during the day, grogginess, anxiety, depression, tremors, numbness, weakness, burning and tingling (pins and needles), hearing loss, and auditory processing (difficulty understanding what was said to you).
  • Genitourinary symptoms include bladder pain, painful urination, painful intercourse/sexual activities, painful or irregular menstrual cycle (periods), and excessive or inadequate urination (too much or too little urine produced).
  • Respiratory symptoms include cough, excessive phlegm, wheezing, runny nose, sinus congestion, sneezing, and swelling of the airway.
  • General symptoms include fatigue, lack of stamina, difficulty exercising, itchy or watery eyes, and bruising easily.
  • There are some additional symptoms that I have observed in a large number of people that are not classically considered mast cell symptoms, but I now firmly believe them to be. One is fever. I think discoloration of the skin may be mast cell related for some people. Another is dystonia, involuntary muscle contraction, which can mimic appearance of a seizure. There are also different seizure-type episodes that may occur due to the nervous system being overactive. I am reluctant to call them pseudoseizures because that term specifically means they are caused as a result of mental illness. I have no evidence that these seizure-type episodes in mast cell patients occur due to mental illness. I personally refer to them as “mast cell derived seizures.” (For people who are wondering, I have been heavily researching this phenomenon and have some theories about why this happens. It’s not fleshed out enough yet to post but it’s on my think list.)
  • Having mast cell disease can make you more likely to have other conditions that cause symptoms.
  • I’m sure there are other symptoms I have forgotten to mention.

7. Why are skin and GI symptoms so common?

  • The skin has a lot of mast cells relative to other tissues. Your skin also comes into contact with lots of things in the environment. Think about the things your skin touches on a daily basis! It makes sense that it would get the exposure so skin symptoms can be common. Additionally, some of the chemicals mast cells release can cause fluid to become trapped in the skin. For these reasons, symptoms affecting the skin are pretty common.
  • The GI tract also has a lot of mast cells relative to other tissues. Your GI tract also comes in contact with lots of things in the environment. Let’s think about this for a minute. Your GI tract is essentially one long tube through your body. You put things from the environment in your GI tract at the top and they come back out the bottom of the tract. In a way, your GI tract is kind of like the outside of the inside of your body.
  • This is the analogy I learned in anatomy and physiology class to visualizing the GI tract as the outside of the inside of the body. Think of the body as a donut. (A low histamine, fully allergy friendly, requires no GI motility, wonderful donut.) Now think of the GI tract as the donut hole. You can put your finger through the hole in the middle of the donut. Only that center part of the donut will touch your finger. This is kind of like putting food throughout the GI tract. That food only touches a very small part of the body as it passes through.
  • Since what we put into our mouths (or other GI openings) is from the outside, your body has many mast cells in the GI tract to protect the body. Some of the chemicals mast cells release can cause fluid to become trapped in the layers of GI tissue. Some of the medications we take for mast cell disease can affect the GI tract. Some of them change how much acid we make in our stomachs. Some of them slow down the GI tract. A few of them speed it up or make the GI tract more fragile. For these reasons, symptoms affecting the GI tract are very common.

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

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

 

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 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 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.