Mast Attack

March 2015: Post summaries and take home points

by Lisa Klimas
June 24, 2015July 16, 2016

Allergic effector unit: The interactions between mast cells and eosinophils

Eosinophils are white blood cells that have granules like mast cells.
Mast cells and eosinophils are often found together in late and chronic stages of allergic inflammation.
Mast cells, eosinophils and their effects on the body are collectively called “the allergic effector unit”.
Mast cells release signals that affect eosinophil behavior and receive signals from eosinophils. The reverse is also true.
Mast cells and eosinophils can activate each other and cause mediator release.
Eosinophils make mast cells more responsive to IgE.
When mast cells and eosinophils are in contact, eosinophils live longer than usual.

Mast cell mediators: Sphingosine-1-phosphate

S1P is involved in development of vessels, vascular permeability and immune function.
Receptors for S1P are found on many cell types, including mast cells.
When the IgE receptor on mast cells is stimulated, S1P is produced and secreted.
Histamine can stimulate S1P production.
S1P regulates blood pressure and heart rate.
S1P is involved in anaphylaxis recovery and probably helps to counteract low blood pressure.

Allergic to infections: Other behaviors of toll like receptors

Toll like receptors (TLRs) are receptors that bind products from bacteria, fungi and viruses to fight infection.
TLRs are found on mast cells.
When TLRs are bound, mast cells secrete inflammatory molecules like TNF, IL-6, IL-13 and IL-1b.
TLRs function independently of IgE.

Leptin: the obesity hormone released by mast cells

Leptin is a hormone mostly released by adipose tissue, but also by mast cells.
Leptin is a “starvation” signal sent to the brain.
Patients with obesity have higher circulatory leptin than those without obesity.
Patients with obesity are more resistant to the effects of leptin, so they often feel hungry even if they have eaten.
Leptin actives inflammatory cells and induces production of TNF, IL-2 and IL-6.
Leptin suppresses signals from the IgE receptor to make mediators.
High levels of leptin may suppress ghrelin, the “hunger” hormone.

Allergic to infections: How bacteria, viruses and fungi activate mast cells

TLRs are found on several cell types, including mast cells.
Unlike many receptors that only have one “matching” molecule, TLRs bind lots of molecules.
These molecules are usually from infecting organisms.
Some molecules induce production of cytokines.
Some molecules, like peptidoglycan from bacterial cell walls, may induce degranulation.
Viral, fungal and bacterial infections can all cause mast cell activation.

Diabetes, steroids and hypoglycemia

High levels of glucocorticoids deplete mast cell populations.
Glucocorticoids interfere with production and release of stem cell factor, a mast cell growth factor.
Glucocorticoids decrease mast cell growth and activity.
The mechanism by which this occurs is thought to involve insulin.
Insulin activates mast cell signaling pathways.
Activity in the HPA axis, which regulates steroid levels, is increased in type I and II diabetes, causing elevated cortisol.
Hypoglycemia can cause mast cell degranulation.
Anaphylaxis can cause hypoglycemia.

Diabetes, mast cells and allergic disease

Type I and II diabetes can protect against anaphylaxis and allergic reactions.
Mast cells are involved in development of glucose intolerance and insulin resistance.
In mice with type II diabetes, mast cell stabilizers protects against glucose intolerance and insulin resistance.
In a patient with type II diabetes, treatment with cromolyn normalized plasma glucose and A1C.
Type I diabetes has a more complicated relationship with mast cells.
Diabetes reduces mast cell degranulation.

Questions on bone involvement

Osteosclerosis is hardening of the bones.
Osteoblast is the cell type that makes new bone.
In osteosclerosis, osteoblasts may lay down new bone faster than osteoclasts can eat up old bone.
Osteolysis occurs when abnormal cells grow rapidly and inhibit osteoblasts, and osteoclasts do not work fast enough.
It is not clear if having osteosclerosis makes progression of SM more likely.
People with all forms of SM have been found ot have osteosclerosis.
Osteosclerosis with swelling of liver and spleen, presence of CKIT mutation in multiple cell types and high increase of baseline serum tryptase warrants careful monitoring.
For mast cell disease, large osteolytic lesions are the “worst” bone involvement because it immediately classifies you as ASM.
Multiple bone breaks due to severe osteoporosis also classifies you as ASM.

Bone involvement in ISM, SSM, SM-AHNMD and ASM: More literature review (part 3)

Osteoporosis is the most common form of bone involvement in SM.
Osteoporosis is more common in mast cell patients than in the general population.
Patients with rapidly increasing serum tryptase and those without have similar incidence of osteoporosis.
Patients with rapidly increasing serum tryptase were more likely to develop osteosclerosis during the period of the study.

Bone involvement in ISM, SSM, SM-AHNMD and ASM: Literature review (part 2)

Overall, about half of SM patients have bone involvement.
Markers associated with both bone resorption and bone formation were higher in mastocytosis patients.
Osteoprotegerin is higher in mastocytosis patients. This protein regulates the activity of osteoclasts.
Levels of c-telopeptide were significantly higher in patients with SM-AHNMD and ASM than in ISM or CM.
Presence of skin lesions does not change risk for osteoporosis.
Bone mineral density and serum tryptase do not correlate with serum markers of bone turnover.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

In osteosclerosis, your body makes new bone faster than it resorbs it.
In osteoporosis, your body resorbs bone faster than new bone is made.
In osteolysis, your body resorbs bone faster than new bone is made, but much worse than in osteoporosis.
Both osteoporosis and osteolysis can cause pathological fractures.
Osteoporosis does not classify you as having ASM.
Osteoporosis that caused multiple fractures classifies you as having ASM.

February 2015: Post summaries and take home points

by Lisa Klimas
June 22, 2015July 16, 2016

How to activate mast cells: Complement protein C3a

The complement system is part of the immune system. It allows infecting organisms to be more readily found and destroyed by the immune system.
Mast cells express a receptor for C3a, a fragment produced during activation of the immune system.
C3a is an anaphylatoxin. It participates in exaggerating the anaphylactic response.
C3a increases vascular permeability, causes smooth muscle contraction, and draws white blood cells to inflamed spaces.
In mucosal mast cells (GI mucosa), C3a inhibits histamine and TNF release.
In serosal mast cells (skin, peritoneum, respiratory tract), C3a induces degranulation when stimulated by IgE or IgG.
Inhaled allergens activate complement system in mucosa of respiratory tract, resulting in formation of C3a.
Tryptase can change C3 to C3a.

Corticotropin releasing hormone, cortisol and mast cells

The term HPA axis refers to the mechanisms by which the hypothalamus, pituitary gland and adrenal glands control each other.
The HPA axis regulates many things, including the stress response, immune modulation, emotions, sexuality and digestion.
The hypothalamus is in the brain. It turns signals from the nervous system into endocrine signals that allow changes by using hormones.
The hypothalamus makes corticotropin releasing hormone (CRH).
The pituitary gland makes and releases many hormones, including adrenocorticotropic hormone (ACTH), thyroid stimulating hormone, growth hormone and others.
When the pituitary gland receives signals from the hypothalamus, it releases these hormones.
CRH from the hypothalamus stimulates the pituitary to produce ACTH.
The adrenal glands make and release cortisol, epinephrine, norepinephrine and other molecules in response to hormones from the pituitary.
ACTH from the pituitary stimulates the adrenals to produce cortisol.
Cortisol tells the hypothalamus to stop releasing CRH and the pituitary to stop making ACTH.
Taking steroids regularly suppresses ACTH so your body stops making its own steroids. This is weaning steroids is important.
CRH is released in response to stress, such as anaphylaxis.
CRH can bind to mast cells and cause release of VEGF.
CRH is also released by mast cells.

January 2015: Post summaries and take home points

by Lisa Klimas
June 20, 2015July 16, 2016

Mast cell mutations: JAK2 and myeloproliferative neoplasms

JAK2 is a helper protein that helps other molecules send signals to make more cells and to increase inflammation.
JAK2 mutation V617F makes some cells more responsive to growth factors, so they grow too much. These cells include red blood cells, platelets and mast cells.
Marker associated with other myeloproliferative diseases essential thrombocythemia (too many platelets), polycythemia vera (too many red blood cells), myelofibrosis (fibrosis of bone marrow).
About 5% of SM patients have JAK2 V617F mutation. Indicates higher probability of developing another myeloproliferative disease.
Doesn’t necessary mean lifespan is shorter.

Heritable mutations in mastocytosis

About 75% of MCAD patients have at least one first degree relative with MCAD.
The CKIT D816V mutation is not known to be heritable, but other CKIT mutations have been found in multiple family members.

Progression of mast cell diseases (Part 1)

Life expectancy with indolent systemic mastocytosis (ISM) is normal.
Average age at diagnosis of ISM is 49.
Type and severity of symptoms vary and do not correlate with disease type, presence of CKIT D816V mutation or tryptase level.
Mediator related symptoms are not indicative of aggressive or progressing disease.
Organ swelling is not always indicative of ASM. Organs can be swollen for many years without functional damage or C findings.

Progression of mast cell diseases (Part 2)

5-10 years from diagnosis with ISM, 1.7% of patients progressed to SSM/ASM.
20-25 years from diagnosis with ISM, 8.5% of patients progressed to SSM/ASM.
Risk of transformation of ISM to acute leukemia or ASM was less than 1% and 3% respectively.
ASM and MCL are associated with accumulation of neoplastic mast cells in organs, impairment of organ function, drug resistance, poor prognosis and organ failure.
In most SSM patients, disease stays stable over years or decades.
SSM patients have higher incidence of anemia, constitutional symptoms and mast cell mediator levels than ISM patients.
SSM is diagnosed later than ISM, around 64 years.
ASM can be slow progressing and stable for many years or rapidly progressing.
During progression of ASM and MCL, some patients lose the CKIT D816V mutation.
Slow progression ASM can be kept under control for several months or even years with interferon and cladribine.
In a group of 342 patients, 0.6% ISM patients developed MCL or AML, 6.5% ASM, and 13% SM-AHNMD.
It is possible for disease to convert to less severe category.

Progression of mast cell diseases (Part 3)

Mast cell accumulation is mostly due to decrease in apoptosis (cell death) rather than excessive proliferation.
20-30% of SM patients have tryptase below 20 ng/ml.
If you test negative for CKIT D816V in blood, you may still be positive.
Bone marrow test for CKIT D816V is most accurate.
Histamine intolerance has been proposed as deficiency of enzymes to metabolize histamine. There is no evidence that this occurs in mast cell disease.
33% of MCAS patients are positive for elevated tryptase, 56% n-methylhistamine, 44% PGD2.
66% of patients with MCAS have major or complete regression in symptoms after one year of treatment.

Progression of mast cell diseases (Part 4)

ISM is not life threatening in and of itself. Anaphylaxis, a symptom of ISM, is life threatening.
49% of SM patients experience anaphylaxis in their lifetime. 48% of anaphylaxis episodes in ISM patients were severe.
There is no consensus on what is a normal count of mast cells in GI tract. Some healthy patients have more than 20 mast cells/hpf.
Most patients with adult onset cutaneous mastocytosis also have systemic mastocytosis.
Early studies indicated CM and MCAD were different, but frequency of CKIT mutations the same in patients with CM, SM and MCAS (about 86% in each group in one study). NOTE: The CKIT mutations were not always the D816V mutation.
Patients with MMAS (monoclonal mast cell activation syndrome) and MCAS (mast cell activation syndrome) never have CM.
ASM and MCL patients frequently lack CM.

Progression of mast cell diseases (Part 5)

55% of pediatric mastocytosis cases occur in the first two years of life.
35% occur between ages of 15 and 18.
Cutaneous mastocytosis can result in mediator release symptoms without having systemic mastocytosis.
2/3 of childhood mastocytosis patients had complete resolution of cutaneous disease and symptoms before adulthood. They were not treated with steroids, PUVA or chemo drugs.
Bone marrow biopsies of children with CM often show more mast cells than normal. High bone marrow mast cells in these children does not affect resolution.
In a study of 50 pediatric CM patients, 86% had a CKIT mutation and36% had the D816V mutation.

Mast cell mutations: TET2 and mutation profiles of aggressive subtypes

TET2 is mutated in 20.8-29% of SM patients.
Several mutations are seen.
TET2 is involved in DNA methylation which affects gene expression.
96% of SM patients with major blood abnormalities had mutations in at least two genes regardless of SM subtype.

Mast cell mutations: SRSF2 in SM-AHNMD

SRSF2 is a protein that affects gene expression.
An SRSF2 mutation was found in 24-37% of SM patients.
Most common mutation in SM after CKIT D816V.
Strongly associated with SM-AHNMD.
Also found in other cell types besides mast cells. In SM-AHNMD, may cause both mast cell disease and associated blood disorder.

Anticholinergic use and dementia

People who took higher amounts of anticholinergics had an increased risk of dementia.
Some medications used to treat mast cell disease are strong anticholinergics, like diphenhydramine and doxepin.
It is not clear if the medications caused dementia or if the conditions that required those medications caused dementia.

Mast cells in wound healing

by Lisa Klimas
June 17, 2015July 16, 2016

One of the most well described non-allergic functions of the mast cell is wound healing. Mast cells are involved in many functions integral to remodeling and closing wounds.

Immediately following formation of a wound, signals are sent to constrict vessels near the injury to decrease the risk of bleeding and infection. After bleeding has been minimized, the blood vessels become a little more permeable to let cells and molecules from the bloodstream into the injured area in order to promote healing and prevent infection. These actions activate the complement clotting system, which produces molecules C3a and C5a. These molecules bind to mast cells and induce degranulation.

Following degranulation, vessels become more permeable through the action of histamine and other mediators. Fibrinogen, important in clot formation, leaves the blood stream and accumulates in the tissue. This triggers thrombin to change fibrinogen to fibrin, forming a clot. Mast cells are active in preventing excessive clotting. Tryptase and heparin are released from granules bound together, and this complex degrades fibrogen and inactivates thrombin.

The extracellular matrix is the structures which give substance to groups of cells and vessels. Following wound formation, fibronectin and type III collagen molecules gather near the injury. Mast cell proteases chymase and tryptase break down the extracellular matrix molecules to make room for newly made cells to close the wound. It is also possible that mast cell mediator CMA1 breaks down fibronectin.

Granulation tissue forms when wounds are healing. Granulation involves several activities, such as cell proliferation, develop of blood vessels, and building of new skin. Fibroblasts, which make collagen and extracellular matrix molecules, are drawn to the injury by mast cell signaling. Once there, they are induced to proliferate by action of the presence of histamine, tryptase, heparin and fibroblast growth factor. Mast cell degranulation also drives generation of new blood vessels through action of histamine, heparin, chymase, fibroblast growth factor, VEGF and tumor necrosis factor. Formation and proliferation of new epithelial tissue is also encouraged by TGF-b1, histamine, IL-1a, IL-1b, IL-6, tryptase, and heparin.

Once enough new cells have been made, the fibroblasts become myofibroblasts to make new muscle. Histamine and tryptase mediate this step. The fibroblasts directly interact with mast cells. Mast cell proteases tryptase and chymase trigger the activation of several molecules that mediate remodeling of the extracellular matrix. The wound is closed following this remodeling and laying down of new skin.

References:

Douaiher, Jeffrey, et al. Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing Advances in Immunology, Volume 122 (2014): Chapter 6.

Christine Möller Westerberg, Erik Ullerås, Gunnar Nilsson. Differentiation of mast cell subpopulations from mouse embryonic stem cells. Journal of Immunological Methods 382 (2012) 160–166.

The high water mark

by Lisa Klimas
June 16, 2015July 16, 2016

I spent most of the latter half of May in bed. People woke me up take medication on schedule and I fed myself small meals periodically. I watched movies and TV and drifted in and out of sleep, pain killers and Benadryl making the world soft around the edges.

Every day, even as I felt myself healing, my strength and stamina waned. My legs felt weak when I stood up. I got winded walking around the block. Holding my head up felt difficult. All of the stamina I had built up before surgery was gone. All of my progress was undone.

I spend so much energy trying to get somewhere I’m never going to get – to this place of physical health where I can exercise and sleep at night and wake in the morning without bleary eyes and a pounding headache. I have been trying to reach this milestone since well before I knew I was sick.

I’m not even sure I know the closest I ever came. What is the highwater mark of this particular struggle? Was it the few weeks before my last birthday when I was sleeping at night and waking without an alarm? Or that really good day last September? The few weeks after my colostomy healed? I don’t know. I’m not sure there is a high water mark. Everything is relative.

Living with a sickness that causes regular setbacks – and requires treatments that sometimes do the same – is difficult. This halting start has become a sort of rhythm, the timing an inherent part of this experience. I’m never getting anywhere. I’m always getting it wrong. It feels like if I could do the right things in the right order that it would make a difference. `

But what if every time I started again, it didn’t mean that every time before was a failure? All those times before, all the moves in the wrong order, kept me alive and participating in the world. How wrong could they be? What if the high water mark of this struggle is just being alive?

Reversing the ostomy was the right move. I am noticeably less inflamed and my body is responding. I am having fewer reactions. I am eating without vomiting. The squishiness, the swelling weight is melting away so I can see the features beneath. I am still in pain, but I think I always will be.

I’m getting stronger. It’s slow, but it’s happening. I can walk for twenty minutes now, Astoria happily padding along beside me. I’m short of breath and sweaty when I’m done, but I can do it.

Maybe it’s time to stop blaming myself for all the times I had to start over. Maybe it’s time to see these setbacks as opportunities to understand my body and learn from it.

Maybe this is enough.

Angioedema: Part 4

by Lisa Klimas
June 15, 2015July 16, 2016

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

by Lisa Klimas
June 13, 2015July 16, 2016

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

by Lisa Klimas
June 11, 2015July 16, 2016

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.