September 2014: Post summaries and take home points

Effects of estrogen and progesterone and the role of mast cells in pregnancy

  • Estrogen and progesterone have many functions in the reproductive system and outside of the reproductive system.
  • The activity of progesterone is amplified by estrogen.
  • Estrogen levels can make cells more responsive to progesterone.
  • Mast cells express receptors for both estrogen and progesterone.
  • Estrogen and progesterone both induce mast cell degranulation individually.
  • Estrogen and progesterone together induce more mast cell degranulation.
  • During pregnancy, secretion of histamine by uterine mast cells is induced.
  • Mast cell degranulation increases uterine contractility.
  • Allergic reactions can induce uterine contractions.
  • Severe allergic reactions may be responsible for pre-term labor.
  • Asthmatic pregnant women are at higher risk of pre-eclampsia.
  • 30-40% asthmatic women have more symptoms during premenstrual period.
  • Women taking hormone replacement have higher risk of new onset asthma.
  • Many women with mast cell disease report more degranulation when menstruating.
  • A 2011 study found that only 6.7% of women with SM delivered prematurely, compared to 7.4% in the general population.

Mastocytic enterocolitis

  • First named in 2006.
  • Refers to having increased mast cells in the GI tract mucosa.
  • Usually causes chronic diarrhea and abdominal pain.
  • Increase in mast cells not associated with SM or CM.
  • The original paper defined mastocytic enterocolitis as more than 20 mast cells/hpf.
  • However, there is not a consensus on what is a “normal” amount of mast cells in the GI mucosa.
  • Some healthy controls have more than 20 mast cells/hpf.
  • Some MCAS patients have mast cell counts in GI tract of 17-23/hpf.

Gastrointestinal manifestations of SM: Part 1

  • 80% of SM patients experience GI symptoms.
  • 11% have GI bleeding.
  • Abdominal pain in SM is usually either upper abdominal pain or lower abdominal cramping.
  • 23% of SM patients have peptic ulcer disease.
  • 85-100% of SM patients have elevated histamine production.
  • Some SM patients produce too much acid, some too little, and some normal amount.
  • In those who overproduce, the levels can be extremely high.
  • 28% of SM patients have esophageal abnormalities.

Gastrointestinal manifestations of SM: Part 2

  • Thought that at least 30% SM patients have abnormalities in small bowel.
  • Many types of abnormalities in GI biopsies of SM patients.
  • 5-25% of SM patients have malabsorption due to small intestine defects.
  • One study found 67% of SM patients have elevated fat excretion in feces.
  • SM patients may have malabsorption of fat soluble vitamins.
  • 20% of SM patients have colon abnormalities.
  • 19% of SM patients have had diverticulitis.
  • Elevated PGD2 may cause diarrhea.

MCAD, MCAS and the hierarchy of mast cell disease classifications

  • MCAD (mast cell activation disease) is a catch-all term for mast cell disease.
  • MCAS (mast cell activation syndrome) is the diagnosis you get if you have evidence of elevated mediator release but don’t meet the criteria for other mast cell diseases.
  • If you have UP: you have UP, you have CM, you have MCAD.
  • If you have TMEP: you have TMEP, you have CM, you have MCAD.
  • If you have SM: you have SM, you have MCAD.
  • If you have SM with UP: you have SM with skin involvement, you have UP, you have MCAD.
  • If you have SM with TMEP: you have SM with skin involvement, you have TMEP, you have MCAD.
  • If you have SM-AHNMD: you have SM-AHNMD, you have MCAD.
  • If you have ASM: you have ASM, you have MCAD.
  • If you have MCL: you have MCL, you have MCAD.
  • If you have MCAS: you have MCAS, you have MCAD.

Neurologic symptoms of mast cell disease

  • Syncope (fainting) affects 14.3% of mastocytosis patients.
  • 6% had back pain.
  • Compression fracture is a common cause of back pain.
  • 35% had headaches.
  • Some mastocytosis patients have migraines.
  • Trigeminal neuralgia has been reported in some patients.
  • 3% of mastocytosis patients develop multiple sclerosis, compared to 0.1% of the general population.

Mast cell disease and chronic constipation

  • Diarrhea or constipation can affect mast cell patients.
  • In one study, 57% of SM patients reported at least two pseudoobstructions a year.
  • Bowel retraining is a good option for managing chronic constipation.
  • People with chronic constipation may have pelvic floor dysfunction.
  • Pelvic floor PT may help.
  • Anorectal manometry and bowel transit time tests are helpful for identifying a cause for constipation.
  • Straining to stool causes long term nerve damage, hemorrhoids, bleeding and fissures.
  • Bowel obstructions can cause rupture and are serious.
  • Many mast cell medications slow GI motility, complicating the constipation issue.

Mast cell look alikes

  • A number of conditions present similarly to mast cell disease.
  • Carcinoid tumors are slow-growing neuroendocrine tumors that may release excessive serotonin.
  • Carcinoid syndrome is diagnosed with a 24-hour urine test for 5-HIAA, a metabolite of serotonin.
  • Pheochromocytomas are neuroendocrine tumors of the adrenal gland that secrete a lot of norepinephrine.
  • Pheochromocytoma is diagnosed with 24-hour urine test for catecholamines and metanephrines.
  • Medullary thyroid cancer produces excessive calcitonin.
  • Medullary thyroid cancer is diagnosed by serum calcitonin.
  • Dysautonomia is an inherent dysfunction of the autonomic nervous system, which can cause wide ranging symptoms.
  • Dysautonomia can be secondary to another condition, like mast cell disease, or a primary condition.
  • Primary asthma can cause airway symptoms.
  • Vocal cord dysfunction can cause airway obstruction.
  • Angioedema causes swelling of any part of the body. It can be hereditary or not.
  • Irritable bowel syndrome is a diagnosis of exclusion.
  • Mast cell disease is often mistaken for anxiety or panic attacks.

Hemolytic anemia

  • A type of anemia that causes abnormal destruction of red blood cells.
  • This causes the body to break down more hemoglobin than usual.
  • Can cause high concentration of reticulocytes (immature red cells) in the blood.
  • Can have many causes, including genetic issues, certain infections, and autoimmune disease.
  • Diagnosed with blood smears. Further testing can reveal specific type.
  • Transfusions can be required in severe cases.
  • If autoimmune, long term steroids or spleen removal are sometimes necessary.

 

Independence Day

I live my life as a series of wagers. A lot of these wagers involve my health. I bet that I can fly if I take enough steroids. I bet that I will get better if I get an ostomy. I bet that I will be more stable if I use IV hydration. I bet that taking this med or that will make me less tired. Sometimes I win. Sometimes I don’t.

The last 18 months of my life have all been one large scale bet. It has been many months of moving the pieces around and trying to shove them into place. It has been emotional and stressful and scary.

I slept through the four weeks following my surgery. I did some other things too, but mostly I slept. One day while I was resting in bed, it occurred to me that all of the strength and stamina I had lost was perhaps for the best. There are few opportunities to reset your body and this was one of them. I wasn’t reacting because I was heavily medicating and resting most of the time. I realized that this might be an opportunity to rebuild my body in a calculated way.

Once I was cleared by my surgeon to exercise, I started an exercise program designed for POTS patients. It was pretty detailed (I’ll do a separate post about this) but involved cardio exercise 3-4 days a week. I haven’t been able to do cardio in years. But I figured it was worth a shot.

The first two weeks were brutally hard. Then it got easier. I am now on the sixth week of a twelve week program. For the first time in many years, I can do cardio (with premedication in a controlled environment) without having a reaction.

I went back to work last week. I took the train to and from work on Monday, Wednesday and Thursday, which also involves about a mile and a half of walking each day. It was pouring torrentially on Wednesday and hot as hell on Thursday. I was exhausted when I got home but I managed to get through each day without napping. I slept every night last week. Getting myself to and from work is a level of independence I have not achieved in a year.

I very rarely drive anymore because I can’t use some of my medications if I need to drive and I have been so reactive that that might have been dangerous. But I made a huge wager on Saturday: I drove myself an hour away to New Hampshire to celebrate the Fourth of July with my friends and nieces. I stayed overnight and went swimming today, deaccessing and reaccessing my port. I drove myself home after being in cold water and direct sunlight for over an hour, stopping at Whole Foods and doing my grocery shopping on the way. I cleaned my apartment, did laundry, made lunch for tomorrow, ironed my work clothes, and watched Shark Week. I did all these things without any help.

The Fourth of July is Independence Day in the US. As I watched the fireworks, it felt like I was celebrating my own personal Day of Independence. I don’t know how long this will last.  But I got this one great week and this one Fourth of July.  And maybe I’ll get more.

October 2014: Post summaries and take home points

MCAS: Treatments

  • MCAS is generally treated identically to ISM.
  • Most cell medications act in one of the following ways:
  • Block the action of released mediators
  • Prevent the release of mediators
  • Prevent production of mediators
  • Any medication that causes a reaction should be evaluated to determine if the reaction is to the drug, a dye or a filler.
  • New medications are usually trialed for 1-2 months to see if they are effective.
  • Antihistamines are first line medications for acute and chronic management of symptoms.
  • Currently available antihistamines either block the H1 or H2 receptor.
  • Most mast cell patients take daily H1 and H2 medications to give baseline coverage.
  • Second generation H1 antihistamines are usually used for daily dosing as they are not sedating and have fewer side effects.
  • No second generation H1 antihistamines are available in IV or IM form, so Benadryl should be used in emergent situations.
  • Tricyclic antidepressants, phenothiazine antiemetics and quetiapine are H1 blockers.
  • Ketotifen is both an H1 antihistamine and a mast cell stabilizer.
  • Ketotifen is not approved for oral use in the US, but can be obtained through compounding pharmacies.
  • Benzodiazepines act on mast cells and GI tract in beneficial ways.
  • Imidazopyridine medications like zolpidem (Ambien) also act on benzodiazepine receptors.
  • NSAIDs can be helpful if patients tolerate them.
  • Aspirin and other NSAIDs interfere with prostaglandin production.
  • Non enteric coated aspirin seems to be better tolerated and more effective for mast cell symptom relief than enteric coated.
  • Leukotriene inhibitors are often used.
  • Cromolyn is the most well known mast cell stabilizer.
  • Cromolyn is poorly absorbed.
  • Many patients have flare of symptoms when starting cromolyn.
  • Pentosan is a mast cell stabilizer that works on the urinary tract.
  • Quercetin is a mast cell stabilizer that interferes with mediator production.
  • Pancreatic enzymes like Creon can help with chronic diarrhea, weight loss and malabsorption.
  • Corticosteroids like prednisone interfere with mediator production but long term use can have severe side effects.
  • Omaluzimab is an anti-IgE antibody. It has been reported by some mast cell patients to reduce reactions.
  • Use of chemo medications for severe MCAS cases has been described in literature.
  • IV hydration is sometimes used to manage baseline MCAS symptoms.
  • TNF inhibitors and interleukin blockers have been suggested as possible treatments.

MCAS: Neurologic and psychiatric symptoms

  • Headaches, dizziness, lightheadedness, weakness, vertigo and feeling about to faint are all common.
  • Sensory and motor nerves may be overactive, causing tingling, numbness, paresthesia and tics.
  • Prostaglandin D2 participates in nerve damage and may cause neurologic symptoms in MCAS.
  • MCAS patients often have unusually deep sleep, also known as mast cell coma, probably from PGD2.
  • Cognitive and mood disturbances can be caused by mast cell degranulation.
  • Psychiatric symptoms in mastocytosis first reported as mixed organic brain syndrome.
  • These symptoms are often effectively managed with mast cell medications.
  • PTSD is not rare in mast cell patients.
  • Autism is increased in patients with mastocytosis and similar reports are surfacing from MCAS patients.

MCAS: Kidney, urinary and genital concerns

  • The GU tract can become easily inflamed in MCAS patients.
  • Vaginal inflammation, painful intercourse and vaginal pain disorders are often found in mast cell patients.
  • Mast cells drive fibrosis when present in kidneys.
  • Fertility issues not rare in mast cell patients.
  • Mast cells are increased and activated in endometrial lesions.
  • Interstitial cystitis is driven by mast cell inflammation.
  • Interstitial cystitis patients often have very high mast counts on bladder biopsy.

MCAS: Anemia and deficiencies

  • Anemia is the most common red blood cell issue in MCAS patients.
  • If anemia is macrocytic, bone marrow biopsy should be performed to rule out myelodysplastic syndrome.
  • Cobalamin is often deficient.
  • Folate deficiency is less common and if present may be due to another hematologic condition, such as hemolytic anemia.
  • Many MCAS patients have selective iron malabsorption.

MCAS: Blood, bone marrow and clotting

  • MCAS does not affect most routine blood tests.
  • Hematologic issues are more common in proliferative mast cell disease, like SM.
  • In previously diagnosed SM patients, bone marrow biopsies were negative 1/6 of the time.
  • When serum tryptase is less than twice the upper limit of normal, BMB is not recommended.
  • MCAS patients may have normal tryptase during reactions.
  • A tryptase level of 20% + 2 ng/ml above baseline indicates activation.
  • MCAS patients may have elevated monocytes, eosinophils and basophils.
  • Reactive lymphocytes may be present in MCAS patients.
  • White blood cell and platelet counts can be high or low in MCAS.
  • Polycythemia vera, a disease characterized by too many red cells, can cause mast cell activation.
  • Poor clotting and easy bruising is often found due to heparin release.
  • Formation of blood clots is not rare in MCAS.
  • Heparin release stimulates formation of bradykinin, which causes angioedema and low blood pressure.

MCAS: Effects on eyes, ears, nose and mouth

  • Eye irritation, excessive tearing, redness, tremors and tics are common.
  • When treated with Botox, the problem often recurs.
  • Difficulty focusing the eyes is common In MCAS.
  • 32% of MCAS patients report eye issues.
  • Middle ear irritation is common and often mistaken for an infection.
  • Hearing abnormalities are common in MCAS and include hearing loss, ringing of the ears and sensitivity to sound.
  • Auditory processing issues are also present in MCAS.
  • Nose bleeds may occur due to heparin release.
  • MCAS patients often have heightened sense of smell.
  • Pain in mouth and lips is common.
  • Taste of metal is common.
  • Ulcerations and sores may look like herpes sores, but when biopsied almost never are.
  • MCAS is associated with burning mouth syndrome.
  • Dental decay despite excellent dental hygiene is not unusual in MCAS.

Kounis Syndrome

  • Kounis Syndrome is also called allergic angina or allergic myocardial infarction.
  • Patients suffer severe chest pain or heart attack due to allergic reactions.
  • Caused by mast cell activation causing spasm of the coronary artery.
  • Over 300 cases in literature.
  • Can occur due to mediator release, formation of blood clot inside a blood vessel near the heart, or due to formation of a blood clot on a stent.
  • Cardiac enzymes and troponins may be normal.
  • Tryptase and histamine are often elevated.
  • EKG and angiogram are often normal.
  • Hypersensitivity myocarditis is a similar phenomenon caused by eosinophils.
  • Treatment requires treatment of both cardiac event and anaphylaxis.

Mast cells and cardiac and vascular dysfunction

  • Mast cells contribute to rupture of atherosclerotic plaques.
  • Histamine is higher in coronary artery of patients who died from coronary heart disease.
  • Higher white blood cell count, platelet and plasma histamine is higher in patients with peripheral vascular disease.
  • Tryptase level correlates to risk of coronary artery disease.
  • Cervistatin and atorvastatin inhibit SCF action on mast cells.
  • Lovastatin inhibited IgE degranulation.

Mast cell mediators: Recommended testing for MCAS diagnosis

  • Serum tryptase
  • Chilled urine for PGD2, PGF2 and n-methylhistamine
  • Some doctors use:
  • Chilled plasma PGD2
  • Plasma histamine
  • Serum chromogranin A
  • Stat chilled plasma heparin

Cardiovascular symptoms of MCAS

  • Heart palpitations and tachycardia are common.
  • Blood pressure may be high or low, often with no trigger.
  • True fainting is uncommon, but feeling about to faint is not.
  • This may be due to POTS or not.
  • When treated for POTS, Afrin reports mast cell patients only see mild reduction in presyncope episodes and little improvement of other symptoms.
  • Chest pain is common, may or may not show changes on EKG.
  • Edema is a common finding.
  • Sclerosis and poor healing is seen in many patients.

Mast cells and metabolic syndrome: Hypertension, obesity and atherosclerosis

  • Inflammation is known to contribute to obesity.
  • Mast cells congregate in larger than normal numbers in fat tissue of obese patients.
  • Obese patients may have higher serum tryptase than patients who are not obese.
  • TNF is released by mast cells.
  • TNF is important in insulin resistance, which contributes to metabolic syndrome.
  • Mast cell stabilizers prevent diet induced obesity and diabetes in animal studies.
  • Obesity is usually associated with metabolic syndrome, but it is also seen in patients who are not obese.
  • Mast cells are involved in obesity, hypertension and atherosclerosis.

Metabolic issues associated with MCAS

  • MCAS patients often have metabolic abnormalities.
  • Vitamin D deficiency is common in MCAS.
  • Hypothyroidism and elevated TSH are often found in MCAS.
  • TPO is often elevated, sometimes without clinical thyroid disease.
  • Elevated ferritin is not unusual in mast cell disease. 18% of ISM patients have it.
  • Elevated ferritin may be confused with hemochromatosis.
  • MCAS is associated with obesity and diabetes mellitus, types I and II.
  • Elevated triglycerides are common.

Genetics of MCAS: mutations and methylation

  • People with MCAS lack the D816V CKIT mutation.
  • Other mutations are often present in CKIT gene of MCAS patients.
  • These mutations are not known to be heritable.
  • Mast cell disease can run in families.
  • Mutations in MCAS CKIT genes are usually heterozygous, meaning there is one mutated copy and one correct copy.
  • Methylation may affect development of MCAS.

Constitutional symptoms of MCAS

  • Fatigue and malaise most common and can be disabling.
  • Chronic fatigue syndrome has been tentatively linked to mast cell activation.
  • Doctors disagree on whether or not fevers are part of MCAS.
  • Excessive sweating is not unusual.
  • A minority of MCAS patients lose weight due to the disease, but weight gain is very common.
  • Bariatric surgery is not usually successful in MCAS patients.
  • Itching is very common.
  • Temperature extremes can trigger mast cell activation.
  • Sensitivity to “harmless” stimuli is common in MCAS.

MCAS and MMAS: Similarities and differences

  • Monoclonal mast cell activation syndrome is marked by presence of 1 or 2 minor criteria for SM.
  • Mast cell activation syndrome meets none of the criteria for SM.
  • Mast cell activation is diagnosed by mediator release testing, response to mast cell mediators and presence of mediator release symptoms in at least two organ systems.
  • 33% of MCAS patients have tryptase >11.4 ng/ml.
  • CM is always absent in MCAS.
  • 46% of MMAS and 21% of MCAS patients have severe anaphylaxis to bee stings.
  • If diagnosed with MCAS or MMAS, bone marrow biopsy is usually recommended if:
  • Baseline tryptase >20 ng/ml
  • Anaphylaxis requiring epinephrine without known cause
  • Abnormal blood counts
  • Unexplained osteoporosis
  • Swelling of liver or spleen

 

 

 

 

Regulation of mast cells by IgE and stem cell factor (SCF)

Mast cells are regulated by two dominant mechanisms. The first is the allergic response via the high affinity IgE receptor. This receptor is called FcεRI. When an IgE molecule binds to this receptor, it triggers the release of calcium in pockets inside the cells, causes the cells to take up more calcium from outside the cell, and changes the cell membrane so that it can degranulate and secrete mediators. There are a number of other things that can affect the strength of the response triggered by FcεRI.

The second mechanism is the survival and activation response when stem cell factor (SCF) binds to the CKIT receptor (also called KIT). SCF is the primary growth and survival factor in non-neoplastic mast cells. In the absence of mast cell disease, it is absolutely required for survival. SCF also attracts mast cells and enhances degranulation from the FcεRI (IgE) receptor, production of cytokines and movement of mast cells from one place to another.

When SCF is increased in tissues, it increases the amount of mast cells there, how long they live and what roles they play. It also increases mast cell responsiveness. In some instances, SCF can directly cause degranulation with IgE involvement.

Despite understanding the importance of SCF, it is not well understood what happens after SCF binds to the CKIT receptor. We know that it increases survival and proliferation, but it’s not clear how. It is possible that the concentration of SCF or CKIT may play a role.

In tissues, mast cells often exist as a part of a membrane, and SCF is important in mast cell adhesion to other cells. When SCF is part of that membrane, it can increase histamine and eotaxin production in mast cells.

Monomeric IgE is IgE that is not bound to an allergen. In the presence of SCF, monomeric IgE can directly cause release of histamine, LTC4 and IL-8. It also makes mast cells more reactive.   When monomeric IgE binds to the FcεRI (IgE) receptor without SCF present, it causes production of IL-6 but not degranulation. However, IL-6 promotes mast cell survival.

References:

Cruse, G., Bradding, P. Mast cells in airway dieases and institial lung disease. Eur J Pharmacol (2015).

River, K., Gilfillian, A.M. Molecular regulation of mast cell activation. J Allergy Clin Immunol 2006, 117, 1214-1225.

Gilfillian, A.M., Beaven, M.A. Regulation of mast cell responses in health and disease. Crit Rev Immunol 2011, 31, 475-529.

 

November 2014: Post summaries and take home points

Food allergy series: Atopy, risk factors and frequency

  • Food allergy generally refers to IgE mediated reactions in literature
  • Other reactions can cause severe food reactions via different mechanisms
  • Food allergy reacts to specific allergen following skin or mucosal contact (mouth, GI tract)
  • Sensitization is when your body makes IgE to something.
  • Allergy is when your body makes IgE to something and that thing makes you sick.
  • Atopy is the tendency of a person to develop allergic diseases like asthma.
  • The term “allergic march” describes progressive accumulation of atopic conditions starting in the first year of life.
  • Allergic march usually begins with atopic dermatitis and progresses to allergic rhinitis, asthma, and food allergy.
  • Severe eczema developed in the first six months of life is associated with increased risk of peanut, milk and egg allergies.
  • Most food allergies are due to egg, cow’s milk, wheat, soy, shellfish, peanuts and tree nuts.
  • 4% of children with food allergies have multiple food allergies.
  • Children with multiple food allergies are most likely to have severe reactions.
  • Adolescents ages 14-17 are more likely to have severe reactions.
  • Peanut, cashews, walnuts and shellfish allergies are most likely to be severe.
  • Largest studies on food allergy use patient reported information which is not the most reliable.
  • Many people eliminate foods from their diets based upon suspicion of allergy. This is usually unnecessary.
  • 89% of patients with atopic dermatitis were shown to have no reactions to suspect foods on oral challenge.
  • 4% of US households had children with multiple food allergies.
  • 3% of US households had children with history of severe allergic reaction.
  • In Canadian households, 8% of people have food allergies.
  • In Australia, 3% of children are allergic to peanuts and 8.9% are allergic to raw eggs.
  • Risk factors for food allergies include:
  • Atopy
  • Low vitamin D
  • Reduced consumption of omega-3 polyunsaturated fatty acids
  • Reduced consumption of antioxidants
  • Increased use of antacids
  • Obesity
  • Increased hygiene
  • Delaying exposure to common allergens
  • Family history of food allergies
  • Specific HLA profiles
  • Male children are more likely to develop food allergies.
  • Black children are most likely to develop food allergies, followed by Asian children, then White children.
  • Children of immigrants in the US are at higher risk than children of American born parents.
  • People living in households earning more than $50,000/yr are more likely to be diagnosed with food allergies.
  • Childhood allergies to milk, egg, wheat and soy are more likely to resolve.
  • Childhood allergies to peanut, tree nut, fish and shellfish are more likely to persist.

MTHFR, folate metabolism and methylation

  • MTHFR stands for methylenetetrahydrofolate reductase.
  • MTHFR is an enzyme involved in folate metabolism.
  • If there is not enough MTHFR, your body cannot break down enough folate.
  • Some folate broken down by your body is used to methylate DNA.
  • DNA methylation is one of the ways your body regulates which genes are turned on and off.
  • A single nucleotide polymorphism (SNP) is a mutation in DNA sequence at one place.
  • SNPs are very common.
  • There are multiple known SNPs that can occur in the MTHFR gene.
  • The two SNPs of interest in the MTHFR gene are called C677T and A1298C.
  • C677T mutation is found in 10% of North Americans, most commonly Hispanics and those of Mediterranean descent.
  • Having two copies of the C677T (called “being homozygous”) can cause mild MTHFR deficiency and result in too much homocysteine.
  • Increased homocysteine has been studied in connection to many conditions but the results are inconclusive.
  • A1298C mutation is not known to elevate homocysteine.
  • A1298C mutation may cause deficiency of BH4, which is important in neurotransmission and formation of nitric oxide.
  • There is no strong support in peer reviewed literature for the association of C677T or A1298C with disease. Many studies contradict each other.
  • There is no known link between MTHFR mutations and mast cell disease.

DNA methylation: How it works

  • DNA methylation is one of the ways your body controls which genes are turned on and off.
  • Methylation is important in cancer.
  • Methylation of tumor suppressor genes causes them to be turned off, resulting in cancers.

Mast cells, heparin and bradykinin: the effects of mast cells on the kinin-kallikrein system

  • The kinin-kallikrein system is a group of hormones that affect inflammation, blood pressure, coagulation and pain perception.
  • It also affects the cardiovascular system, including cardiac failure.
  • This system produces bradykinin.
  • Bradykinin has many functions, including GI contraction, bronchoconstriction, induction of cell proliferation, collagen synthesis and release of many molecules.
  • Bradykinin causes blood vessels to dilate, decreasing blood pressure.
  • Bradykinin affects sodium excretion from the kidneys, further decreasing blood pressure.
  • Bradykinin opposes the action of angiotensin II, which increases blood pressure.
  • Mast cells release bradykinin and molecules to make it.
  • Mast cells also release heparin, which can initiate bradykinin formation.
  • Too much bradykinin causes angioedema.
  • Mast cell degranulation occurs with physical trauma in part due to formation of bradykinin.
  • Bradykinin induces release of histamine, serotonin and other molecules.

Biphasic anaphylaxis

  • Monophasic anaphylaxis is one episode of anaphylaxis symptoms.
  • Biphasic anaphylaxis is a second episode of anaphylaxis symptoms after resolution of symptoms.
  • Late onset anaphylaxis occurs several hours after exposure to trigger.
  • Protracted anaphylaxis is a long episode of anaphylaxis symptoms despite treatment.
  • Higher doses of corticosteroids may decrease incidence of second phase.
  • Studies on frequency of biphasic anaphylaxis differ on rate of incidence, but most report around 20% of patients have biphasic anaphylaxis.
  • Second phase can occur over a day after the first.
  • Biphasic patients had longer lasting initial anaphylaxis reactions.
  • Biphasic patients statistically receive less epinephrine for the initial reaction, which may result in the second reaction.
  • Delay in administration of epinephrine, inadequate dosing of epinephrine and need for large doses of epinephrine make biphasic anaphylaxis more likely.
  • Previous cardiovascular history, older age and use of beta blockers are risk factors for biphasic reactions.
  • Oral ingestion of trigger makes biphasic reactions more likely.
  • Not clear if mastocytosis patients are more likely to experience biphasic reactions.

MCAS: Respiratory symptoms

  • Throat symptoms are common in MCAS.
  • MCAS reactions can cause inability to swallow or breathe due to angioedema.
  • Breathing difficulty requires epinephrine.
  • Low level difficulty of breathing (feeling like you can’t get a deep breath) is the most common MCAS respiratory symptom.
  • Chest x-ray and pulmonary function testing are usually normal in MCAS patients.
  • Prostaglandin D2 is a potent bronchoconstrictor.
  • Allergic asthma is not uncommon in MCAS.

Fragrance allergy

  • Inhalation can cause anaphylaxis.
  • There have been cases of patients who can ingest a food but react to inhalation, such as Baker’s asthma.
  • Fragrance is one of the top five allergens in North American and European countries.
  • Fragrance allergy can cause skin, eye and respiratory problems.
  • Perfume can cause asthma and other respiratory problems through an unclear mechanism.
  • A significant portion of the population reacts adversely to scented products, even when worn by others.
  • 5% of general population found scented products on others to be irritating.
  • 19% had symptoms from exposure to air fresheners.
  • 9% had symptoms from exposure to scented laundry products.
  • Essential oils can cause allergic reactions regardless of the purity.
  • Some essential oils have been tied to severe allergic reactions, such as clove oil.
  • Oils of citrus fruits liberate histamine and cause mast cell symptoms.
  • In mast cell patients, scents can cause severe full body reactions that are potentially life threatening or fatal.

MCAS: Pain

  • MCAS patients may experience many types of pain.
  • Bone pain, osteopenia and osteoporosis are common in MCAS.
  • Joints and soft tissues are often painful.
  • Mast cells are involved in chronic lower back pain and complex regional pain syndrome.
  • Serotonin can amplify pain signals in chronic pain.
  • Increased serotonin and mast cell counts are found in some patients with chronic abdominal pain.
  • 95% of body serotonin is found in the peritoneal cavity.
  • Tricyclic antidepressants inhibit serotonin release and are sometimes used for abdominal pain.

 

 

 

 

 

 

 

 

 

Mast cells in vascular disease: Part 3

Aneurysms are formed when elastic tissue is degraded by proteases and MMPs; the vessel is thinned due to smooth muscle loss; and the endothelium is broken down, resulting in inflammation. There is a significant body of evidence linking aneurysm formation and growth to mast cell activity.

A number of studies have found that mast cells are present in larger numbers in vasculature near aneurysms. Mast cells are increased in cerebral arteries of patients who died from subarachnoid hemorrhage. In particular, mast cell number is higher in arteries close to the rupture site. Mast cell count has been linked previously to aneurysm instability. Another study found that activated mast cells were increased in the aortas of patients who died from abdominal aortic aneurysms. Increased mast cells are also found in ascending aortic aneurysms. Mast cell density is a predictor for occurrence of ascending aortic aneurysm.

Chymase activity has been heavily implicated in aneurysm physiology. One study found that levels of angiotensin II were unlikely to induce development of aneurysm, but that degradation of the vessel by chymase may weaken the aneurysm and increase risk of rupture. Increased chymase activity was found in an additional fourteen patients having aortic aneurysms repaired. In thoracic aortic aneurysm patients, chymase positive mast cells were found in inflamed areas. Chymase may participate in the generation of reactive oxygen species. In abdominal aortic aneurysm samples, most players in the renin-angiotensin system, including chymase and cathepsins, are increased.

Serpin A3, a protease inhibitor, normally regulates activity of elastase, chymase and cathepsin G. It is thought that deficiency of this molecule may worsen damage caused by chymase.

Mast cell proteases, like tryptase and chymase, may be involved in the formation of aneurysms. Erosion of the endothelium occurred in the thrombosed region of the vessel, followed by decreased oxygen supply to the underlying vessel. Tryptase and chymase may participate in rupture of the vessel and intravascular hemorrhage. Adrenomedullin, a mast cell mediator, is found to be strongly expressed in mast cells to local to aneurysms. Adrenomedullin suppresses formation of the extracellular matrix.

Serum tryptase levels in abdominal aortic aneurysms correlated well with growth of aneurysm as well as risk of complications during repair. Tryptase deficient mice were completely protected against developing this type of aneurysm. Tryptase deficiency reduced expression of cathepsins, as well as activation of endothelial cells and movement of monocytes. Tryptase induces release of cathepsins that trigger apoptosis, so this may be a mechanism.

5-lipoxygenase is the enzyme that drives leukotriene formation. Mice deficient in this molecule were protected against aneurysm formation. They also had less inflammation and apoptosis, lower IL-6 and IFN-γ. Mast cell degranulation augmented aneurysm formation while mast cell stabilizer cromolyn decreased it. Another study found that treatment with tranilast, another mast cell stabilizer, decreased the diameter of the aorta.

Leukotriene C4 and 5-lipoxygenase are increased in patients with abdominal aortic aneurysms, but leukotriene B4 is not. Leukotrienes increase release of MMPs and encourage matrix degradation. Leukotrienes may be a therapeutic target to slow aneurysm progression.

References:

Kennedy, Simon, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53-65.

Bot, Ilze, et al. Mast cells: Pivotal players in cardiovascular diseases. Current Cardiology Reviews, 2008, 4, 170-178.

 

Phantom

I have always been fascinated by both the human body and the diseases that affect it. When I was about ten years old, my parents bought me a medical dictionary. I read it cover to cover. I wrote little stories about people with Legionnaire’s Disease and Tetrology of Fallot, describing the symptoms and treatments in vivid detail.

It was in this dictionary that I first read about phantom pain. It always made a weird sort of sense to me. Bodies are creatures of habit, just like us. Of course your body expects to have all of the parts it started with. Of course your brain would assume it was merely misinterpreting signals when suddenly a limb was missing. The alternative was too awful to consider.

It never occurred to me that the body could experience phantom pain from a part of the body that was never supposed to exist. As soon as my epidural line was pulled five days post-op, I started having severe sporadic pain where my stoma used to be. It was distinct from the other pains – the burning in the lower colon, the sharpness in the rectum, the soreness near the incisions.

This was something different. It felt like when my body tried to pass stool through the stoma, but couldn’t because of an obstruction. It was the same exact same sensation. My body remembers the route of a path that should never have been there to begin with.

I lived 29 years without an ostomy. In the two years that I had it, I believed it was the best solution for me, and for most of that time, I believed that I would always have it. The only way to survive was a radical acceptance of this defect. I told myself that this was the best option for my body and I made myself believe it. I believed it so much that even my body was convinced.

I still have a wound where my stoma was. It is closing slowly. Mostly the pain is manageable; I know it will never really go away. Several times a day, I feel my body mimic the pressure of an obstruction behind the stoma, the twisting and lines of pain spiderwebbing into my lower back. The pain isn’t real, but my brain won’t believe it.

Phantom pain is notoriously resistant to pain medication. One of the better options is the use of psychological “tricks” to convince your body that it is still intact. I am thinking about how to do this. But I don’t know which version of my GI tract my brain thinks is real.