July 2015

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.

 

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

 

 

 

 

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.