Lisa Klimas

Mast cells in wound healing
• When a wound occurs, the complement system is activated to form a clot.
• Complement molecules activate mast cells and induce degranulation.
• Mast cells work to prevent excessive clotting.
• Mast cells break down the extracellular matrix to make room for new cells to close the wound.
• Mast cells drive generation of new blood vessels.
• Histamine and tryptase mediate formation of new muscles.
Angioedema: Part 1
• Hereditary angioedema (HAE) is a heritable blood disorder that causes episodes of protracted swelling that can be life threatening.
• Angioedema is when fluid leaves the bloodstream and gets trapped between the deep dermis and subcutaneous tissue.
• Swells can last up to five days.
• About 30% of HAE patients get a pink ring rash.
• HAE patients do not have hives or itching.
• Swelling can affect any part of the body.
• Swelling of the tongue and throat can cause suffocation.
• Abdominal swells are often misinterpreted as “acute abdomen” requiring surgery.
• 85% of patients have type I.
• 15% have type II.
• Type III cases are rare.
• All three are treated similarly.
• Bradykinin causes blood vessels to dilate, decreasing blood pressure and causing fluid to become trapped in tissues.
• C1 inhibitor (C1INH) regulates the C1 protein, which activates the complement system (for fighting infections), controls formation of blood clots and generation of bradykinin.
Angioedema: Part 2
• In HAE type I, C1 inhibitor (C1INH), C4 and C2 levels are low; C1q is normal.
• In HAE type II, C1INH is normal or a little increased, C4 and C2 are low, C1q is normal; C1INH functions poorly.
• In HAE type III, C1INH is normal and functional; C4 may be normal.
• HAE attacks can cause airway constriction leading to suffocation.
• More than half of HAE patients will experience this type of swelling at least once.
• Swells usually last 2-3 days and then resolve.
• Antihistamines and steroids do not resolve this type of swelling.
• HAE has many triggers in common with mast cell disease, including foods, estrogen level, psychological stress and physical triggers.
• Cinryze, Berinert and Ruconest are C1INH solutions for IV use.
• Kalbitor is a kallikrein inhibitor for SQ injection.
• Firazyr is a bradykinin receptor blocker for injection.
• Medications like danazol and tranexamic acid are seeing less use with several new meds available.
Angioedema: Part 3
• Acquired angioedema (AAE) patients have deficiency of C1 esterase inhibitor (C1INH) that is not due to genetic defect.
• AAE is ten times less common than HAE.
• AAE often presents with low CH50, C2, C4 and sometimes C1q, poorly functioning or low C1 esterase inhibitor (C1INH).
• AAE can occur secondary to many autoimmune and hematologic diseases.
• Type I AAE has poor function of C1INH.
• Type II AAE has autoantibodies to C1INH.
• Idiopathic angioedema is three episodes of angioedema in 6-12 months without a clear reason.
• Type III HAE patients sometimes have mutations in the Factor XII gene, but not all.
• Type III patients have four attacks a year on average.
• Estrogen levels are more likely to induce angioedema in Type III patients than in other types of angioedema.
• Bruising and clotting issues are sometimes seen in type III HAE patients.
Angioedema: Part 4
• Deficiencies of complement molecules C1q, C1r, C1s, C2, C4 are associated with lupus like autoimmune conditions.
• Without these molecules, dead cells and debris cannot be removed and cause local inflammation.
• In HAE types I and II, complement molecules C2 and C4 are low.
• Deficiency in C2 and C4 might predispose to autoimmune disease.
• One study found 13.2% HAE patients had autoantibodies to thyroid.
• 47.5-48% of HAE patients had at least one autoantibody when tested with a panel for several autoantibodies.
• On average, 10% of the healthy population has at least one autoantibody.
• 12% of HAE patients had autoimmune disease when tested with a panel for several autoimmune conditions.
• HAE patients often have a decreased sense of smell.
• HAE patients have increased B cell activation and autoreactive B cells, which contributes to autoimmunity.
Activating the complement system: Classical, alternative and lectin pathways
• The complement system is many proteins that can circulate in the bloodstream.
• Other proteins can cut off pieces of these proteins to activate the proteins.
• Once the proteins are activated, they help kill infecting organisms.
• The classical pathway is activated by C1 protein when microbes are present.
• The alternative pathway is activated by the C3 protein changing into C3b.
• The lectin pathway is activated by two proteins called MBL and ficolin binding to the surfaces of microbes.
• These pathways release C3a and C5a, which activate mast cells.
• C1 inhibitor (C1INH) inactivates C1r and C1s to stop the complement pathway.
Deconditioning, orthostatic intolerance, exercise and chronic illness – Part 6
• Exercise can treat deconditioning due to orthostatic intolerance.
• Exercise can also exacerbate symptoms in deconditioned patients.
• It is worse when coupled with hot weather or eating before exercise.
• A sustained hand grip will raise blood pressure for a short time.
• Performing the hand grip when changing position or after exercising or eating can help mitigate OI symptoms.
• Leg crossing while tensing muscles can also help regulate blood pressure before standing.
• Multiple studies have demonstrated that regular exercise can help manage POTS.
• Recumbent exercise is helpful when starting to work out as it is less likely to trigger OI symptoms.
• Some patients are able to recover significant capability and are able to engage in athletic activities.
• Exercise for chronic fatigue and fibromyalgia patients has also had success in improving deconditioning symptoms and quality of life.
Deconditioning, orthostatic intolerance, exercise and chronic illness – Part 7
• Volume expansion (use of IV hydration or volume expander like dextran) can improve symptoms in deconditioned patients.
• Volume expansion does not improve exercise capacity.
• IV saline with exercise gives the best results for symptom relief.
• Volume expansion can mitigate the effect of heat stress on the body.
• Volume expansion alone stabilized blood supply to the head.
• 86% of POTS patients in a study reported IV saline as the best treatment for brain fog.
• Mast cell degranulation can cause hypotension and vasodilation.
• Mast cell mediator release can cause fluid loss from blood resulting in edema.
• Volume loading in the form of IV fluids may decrease mast cell symptoms due to deconditioning, orthostatic intolerance and capillary leakage.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1

• Deconditioning is when the body becomes acclimated to less physical stress and becomes less able to function properly under normal conditions.
• Bed rest can cause deconditioning.
• The cardiovascular system changes within 24 hours of bed rest.
• In less than a week, 10% of blood volume is lost.
• When deconditioned, your body does not make appropriate changes when changing position.
• This is called orthostatic intolerance (OI).
• Chronic illness can cause deconditioning.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2

• Orthostatic intolerance(OI) is symptoms that interfere with or prevent standing up.
• OI affects heart rate, blood pressure and distribution of blood to the brain.
• In OI, the body incorrectly initiates a fight or flight response.
• Orthostatic hypotension is a reduction of systolic blood pressure of more than 20 mm Hg or diastolic blood pressure of more than 10 mm Hg within three minutes of standing.
• POTS patients have daily OI symptoms with excessive tachycardia when standing (increase of 30 bpm when standing or over 120 bpm in adults).
• Postural syncope (fainting) can be caused by orthostatic intolerance or vasovagal syncope (VVS).
• Fainting is caused by lack of blood flow to the brain.
• Mast cell disease is known to cause orthostatic intolerance.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3

• POTS (postural orthostatic tachycardia syndrome) is one type of orthostatic intolerance (OI).
• POTS is characterized by an increase of heart rate of 30 bpm or more when standing in the absence of orthostatic hypotension.
• Neuropathic POTS is caused by the veins in the legs not constricting enough to maintain blood pressure when standing.
• Hyperadrenergic POTS is caused by the nervous system telling the heart to beat faster and harder.
• HyperPOTS patients have fluctuating or elevated blood pressure, tachycardia, hypertension and excessive sweating.
• One study found that 38% of mast cell patients had hyperPOTS.
• One study found that 28.9% of POTS patients had less blood volume than normal.
• POTS patients have persistent tachycardia, push less blood out of the heart per beat than normal, have a smaller than normal part of the heart, and do not use oxygen effectively during exercise.
• POTS is often associated with conditions that provoke exercise intolerance, like fibromyalgia, chronic fatigue syndrome and deconditioning.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4

• Syncope (fainting) is loss of consciousness due to temporary loss of blood supply to the brain.
• About 40% of people will faint in their lifetime.
• Vasovagal syncope(VVS) is a form of orthostatic intolerance (OI).
• VVS is often preceded by lightheadedness, sweating, weakness, nausea and visual disturbances.
• VVS patients can go long periods without OI symptoms.
• Ingestion of 16 oz of water in five minutes effectively treats OI episodes of all types.
• OI symptoms can be triggered by large meals, sudden change in position, extended time laying down, heat and alcohol.
• Physical maneuvers and compression garments can decrease OI symptoms in some patients.
• Increasing salt and water intake is recommended for adults with orthostatic hypotension or POTS.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 5

• Deconditioning and physical inactivity increase risk for cardiovascular disease.
• A person can lose 10-20% of muscle strength in one week of bed rest.
• Muscle loss is greatest in lower back and legs.
• After three days of bed rest, connective tissue and muscles begin to contract.
• Osteoporosis is more likely in deconditioned patients.
• After twelve weeks of bed rest, almost 50% of bone density can be lost.
• Frequent bed rest increases risk of blood clots.
• Bed rest can reduce strength of muscles supporting the respiratory system, leading to cough and pneumonia.
• 15-30% of bedrest patients develop kidney stones.
• Frequent bed rest can cause neurologic, cognitive and psychiatric disturbances.
• Thyroid, adrenal and pituitary hormones become dysregulated with bed rest.

Exercise and mast cell activity

• Exercise induces mast cell degranulation and release of newly made mediators.
• Histamine, tryptase and leukotrienes increase following exercise in patients who have exercise induced bronchoconstriction.
• Treating with montelukast and loratadine suppressed release of histamine and leukotrienes.
• Leptin is elevated in obese patients.
• Leptin makes airways more reactive and more inflamed.
• Leptin increases the allergic response including leukotriene production.
• Asthmatics who are obese are less likely to respond to inhaled corticosteroids but respond to anti-leukotriene medications.
• Leukotriene E4 was elevated in both obese and lean asthmatics after exercise.
• 9a,11b-PGF2 (metabolite of PGD2) was elevated in obese and lean asthmatics after exercise.

Histamine depletion in exercise

• Regular exercise can be protective against asthma.
• Histamine is released in lungs due to exercise.
• Histamine becomes depleted during exercise.
• Plasma epinephrine does not rise in asthmatics following exercise.
• Inhalation of cromolyn before exercise can prevent or mitigate induced asthma in many patients.
• Treating with H1 and H2 antihistamines decreased endurance during exercise.
• Histamine is important in inducing exercise tolerance.

Chronic urticaria and angioedema: Part 3

• There are several pathways that can cause urticaria and angioedema:
• IgE activation of mast cells
• C3a and C5a activation of mast cells
• Production of bradykinin
• IgG activation of mast cells
• NSAIDs
• Non-immunologic methods such as radiocontrast dyes, pressure on the skin, heat, etc.

Chronic urticaria and angioedema: Part 4

• There are several conditions that present similarly to chronic urticaria and angioedema.
• Development of urticaria during pregnancy is not unusual.
• Cutaneous mast cell patients often have urticaria like lesions.
• MCAS can also cause angioedema and urticaria.
• Angioedema in the absence of urticaria is rare.
• Hereditary angioedema (HAE) is caused by deficiency or dysfunction of C1 esterase inhibitor in most patients.
• HAE patients do not have coincident urticaria.
• Acquired angioedema is caused by antibodies to the C1 esterase inhibitor, which can be from cancer.
• Angioedema can affect any part of the body.

Chronic urticaria and angioedema: Part 5

• Treatment scheme:
• Second generation H1 antihistamine
• Increase dose of second generation H1 antihistamine
• Add another second generation H1 antihistamine
• Add an H2 antihistamine
• Add a leukotriene receptor antagonist.
• Add a first generation H1 at bedtime.
• Add a strong antihistamine like hydroxyzine.
• Consider Xolair or immunosuppressants.

Premedication and surgical concerns in mast cell patients

• Exact incidence of immediate anaphylaxis from surgery or anesthesia is unknown in mast cell patients
• Mast cell patients should premedicate for surgery.
• Anxiety, temperature changes, irritation of skin, physical trauma and pain can all cause mast cell activation.

Mast cell disease and the spleen

• The spleen removes old or damaged red blood cells.
• It holds a supply of blood cells that can be released in case of hemorrhage.
• It recycles iron from old red blood cells.
• It filters out bacteria.
• When the bone marrow is not producing enough blood cells, the spleen can make red and white blood cells.
• Swelling of the spleen is called splenomegaly.
• If you can feel the spleen, it is at least twice its normal size.
• Swelling of the spleen may have no symptoms, but it can cause referred pain, especially in the shoulder.
• If the bone marrow is not producing enough blood cells, the spleen can become swollen because of the stress of making so many cells.
• Swelling of the spleen is pretty common in blood disorders.
• Swelling of the spleen is a B finding in SM. If you have two B findings, you have smoldering systemic mastocytosis.
• Hypersplenism is when the spleen is working too hard.
• Hypersplenism with splenomegaly is a C finding, which means you have aggressive systemic mastocytosis.
• Hypersplenism is indicated by swelling of the spleen, reduction in red blood cells, platelets or granulocytes, increased cell production by the bone marrow, and probable resolution if the spleen is removed.
• Hypersplenism can cause additional complications like ascites (free fluid in the abdomen) and port hypertension (increased pressure in the vein between the GI tract and spleen).
• Portal hypertension and ascites are also C findings.
• Removal of the spleen can improve prognosis.
• Patients with no spleen are more susceptible to certain types of infections.

Cost of US Healthcare

• In 2010, the US spent an average of $8233 per patient.
• The US spends 17.6% of GDP on healthcare, compared to other developed nations which average 9.5%.
• The US has fewer practicing physicians and fewer hospital beds.
• In the US, we spend 2.5x more on ambulatory care, such as walk-in clinics and emergency rooms.
• We do not have enough PCPs in the US.
• Administrative cost per patient is much higher in the US, partly due to not having electronic records.
• The US performs more tests than other countries.
• Five year survival rates for many cancers are best in the US.
• Access to newer medications and treatments is more readily available in the US.

Third spacing

• The human body keeps fluids in two spaces called compartments.
• The first compartment is inside cells.
• The second compartment is outside of the cells, like in the tissues around the cells.
• The second compartment holds 40% of fluids.
• Third spacing is when your fluids collect outside of one of these two compartments.
• Fluid in a third space is unusable by the body.
• Ascites, pulmonary edema and angioedema are all forms of third spaces.
• Third spacing can compress structures around the fluid.
• Third spacing can sometimes affect organ function.
• Third spacing can cause the fluid level in the circulatory system to drop.
• People with frequent third spacing often have symptoms of dehydration.
• Third spacing can occur due to anaphylaxis or mast cell activation.
• IV fluids are helpful for some patients who have third spacing.

Sex and chronic illness series: Vaginal pain

• Vulvodynia is vulvar pain without an obvious cause.
• Vulvodynia can cause burning, stinging or sharp pain in the vulva, labia and vaginal opening.
• Vaginal penetration can be painful with vulvodynia.
• Any pressure on the genital area, including sitting, can be painful with vulvodynia.
• Vulvar vestibulitis is a subset of vulvodynia found in 10-15% of women who receive regular gynecological care.
• Women with a chronic pain disorder like interstitial cystitis or fibromyalgia are three times more likely to have vulvodynia.
• If they have more than one pain disorder, their risk increases over five fold.
• 73% of vulvodynia have no other known chronic pain disorder.
• Mast cells have been linked to sexual pain disorders.
• Allergic reactions or mast cell degranulation may cause vulvodynia.
• Vulvodynia patients have high numbers of degranulated mast cells in biopsies.
• Wearing cotton underwear and avoiding scented products can help vulvodynia.
• Oxalate rich diets can irritate vulvodynia but do not cause it.
• Creams with cromolyn are effective for vulvodynia pain.
• Physical therapy and biofeedback can help pelvic floor dysfunction.
• If penetration is painful, dilation can be helpful.
• A vestibulectomy is a last resort and is about 80% effective.
• About 116 million people in the US live with chronic pain.

Antibiotics (part one)

• Bacteria are categorized by the way they are shaped and grouped, and how they derive energy.
• Bacteria are also categorized by their reaction to a test called a Gram stain.
• Antibiotics inhibit the growth of or kill microbes, including bacteria.
• Medications that kill fungi are called antimycotics or antifungals.
• Antivirals kill viruses, but viruses are not technically alive.
• Some antibiotics are only effective against specific types of bacteria. These are called “narrow spectrum” antibiotics.
• Some antibiotics are effective against many types of bacteria. These are called “wide spectrum” antibiotics.

Antibiotic resistance (part two)

• It took less than five years for antibiotic resistance to develop to penicillin, the first widely used antibiotic.
• Using antibiotics unnecessarily contributes to antibiotic resistance.
• Antibiotics do not treat viral infections.
• If you get repeat, frequent infections of the same nature, you need to see an infectious disease specialist.

Mast cell leukemia

• Less than 1% of mastocytosis cases are MCL.
• It can occur in a patient who previously had mastocytosis or with no history of mast cell disease.
• MCL patients have bone marrow infiltration of at least 20% mast cells and infiltration of internal organs.
• CKIT D816V mutation is not always present.
• Median survival is six months.
• Swelling of spleen and liver are common in MCL patients.
• Only 1/3 of MCL patients have skin involvement.
• In 25% of MCL cases, CD25 is not expressed; in 33%, neither CD25 nor CD2 is expressed.
• Average age of diagnosis with MCL is 52 years old.
• 27% of patients had a history of mastocytosis.
• Only four cases recorded of children with mastocytosis evolving into MCL.
• In one case, a child with a mastocytoma developed MCL.
• Treatment is largely experimental.
• Seven patients have received stem cell transplants. All have died in less than three years.

Diagnosis of mast cell diseases

• Cutaneous mastocytosis, including UP, TMEP and DCM (diffuse cutaneous mastocytosis), is diagnosed by biopsy.
• Mastocytoma can also be diagnosed by biopsy, but urtication on touching is usually diagnostic.
• SM has one major and four minor criteria. You must meet one major and one minor, or three minor criteria for diagnosis.
• The most common method for diagnosing SM is bone marrow biopsy, but biopsy from any non-skin organ may meet criteria.
• SM patients are biopsy negative 1/6 of the time.
• The blood test for the CKIT D816V mutation is not always reliable. Bone marrow is more reliable.
• Serum tryptase criterion for SM is baseline tryptase, not reaction tryptase.
• There are three criteria for SM called B findings that show disease progression. If you have two or more B findings, you have smoldering systemic mastocytosis.
• There are five criteria for SM called C findings that show aggressive disease. If you have one or more C findings, you have aggressive systemic mastocytosis.
• Mast cell leukemia is usually diagnosed through bone marrow biopsy.
• Mast cell sarcoma is a very aggressive tumor that converts to mast cell leukemia. It is diagnosed by biopsy.
• Mast cell sarcoma is different from mastocytoma.
• Mast cell activation syndrome (MCAS) is diagnosed by evidence of mediator release, presence of mediator release symptoms, response to mast cell medications and absence of another cause for mast cell activation.

Myelodysplastic syndrome (MDS)

• Umbrella term for disorders in which body does not produce enough myeloid cells and the cells produced do not function correctly.
• Myeloid cells are a type of white cells including eosinophils, basophils, neutrophils and mast cells.
• MDS patients have low blood counts.
• Sometimes asymptomatic.
• Spleen is often swollen.
• Bone marrow biopsy is diagnostic.
• There are a number of causes of MDS.
• Stem cell transplant may be considered in severe cases.
• Transplant has 50% survival after 3 years.
• Majority of MDS patients progress to acute myeloid leukemia (AML).
• 23% of SM-AHNMD have SM and MDS.

Cutaneous mastocytosis and systemic symptoms

• Urticaria pigmentosa (UP) and telangiectasia macularis eruptiva perstans (TMEP) are forms of cutaneous mastocytosis (CM).
• CM is caused by dense infiltrates of mast cells in the skin.
• Skin is the organ most likely to be infiltrated by mast cells.
• Patients with UP or TMEP who do not have SM can still have symptoms affecting organs other than the skin.
• CM patients can have shortness of breath, low blood pressure, nausea, vomiting, diarrhea and other mast cell symptoms.
• Mast cell mediators release in the skin can move through the tissue and trigger other mast cells.
• The more skin covered by rash, the more likely systemic reactions are.
• Having systemic symptoms does not mean you have SM.
• If you develop CM as an adult, you are likely to develop SM.
• Chronic elevation of tryptase, expression of CD25 by skin mast cells or presence of D816V CKIT mutation can indicate SM will develop.
• Systemic symptoms in CM are treated the same way as in SM or MCAS.
• MCAS does not refer to a state of reactivity or severe symptoms.

The question I get asked the most

• SM is not cancer.
• It is not cancer because the cells do not proliferative enough to endanger life.
• Most SM patients have indolent disease, for which life expectancy is normal.
• ASM has more features in common with cancer.
• MCL is cancer.

Anticholinergic effects of mast cell medications

• Anticholinergics block the molecule acetylcholine from sending signals in the central and peripheral nervous sytems.
• Blocking acetylcholine can cause many side effects, including:
• Decreased GI motility
• Dry mouth and throat
• Dilation of pupils
• Rapid heart rate
• Visual disturbances
• Urinary retention
• Cognitive issues
• Myoclonic jerks
• A lot of antihistamines are anticholinergics.
• Cyproheptadine, promethazine, desloratadine, loratadine, diphenhydramine, clemastine, doxepin, doxylamine, ipratropium, hydroxyzine and meclizine are anticholinergics.
• Alprazolam, diazepam, ranitidine, prednisone and hydrocortisone may be anticholinergics.
• Cetirizine and fexofenadine are not anticholinergics.

Pregnancy in mastocytosis

• Many allergic conditions are exacerbated by menses.
• Sex hormones influence mast cell activation and degranulation.
• Mastocytosis patients often discontinue antihistamine and antimediator medications during pregnancy.
• During pregnancy, 45% of mastocytosis patients had itching, 40% had flushing, 24% had GI symtpoms, 9% had anaphylaxis.
• 22% had worsened symptoms throughout pregnancy.
• 18% developed new symptoms.
• 33% had improved symptoms during pregnancy.
• 15% had complete resolution of symptoms.
• All resolutions occurred during the first trimester and most lasted throughout the pregnancy.
• Anaphylaxis during pregnancy was resolved without epinephrine.
• 45% had no change in symptoms during pregnancy.
• Anesthesia and medications for labor were safe in mastocytosis patients.
• Premedication at initiation of labor is recommended.
• Rate of prematurity and birth complications were similar to general population.

Histamine effects on neurotransmitters (serotonin, dopamine and norepinephrine)

• Medications that block the H1 receptor increase dopamine release.
• Histamine stimulates prolactin release via the H2 receptor, which inhibits dopamine production.
• Histamine can increase metabolism of norepinephrine, serotonin and dopamine.
• About 40% of serotonin released by mast cells.
• Serotonin causes many GI symptoms.
• Mast cells release dopamine.
• Frequent mast cell activation decreases dopamine production.
• Dopamine can be converted to norepinephrine.
• Dopamine is responsible for cognitive alertness.
• Norepinephrine is responsible for concentration and vigilance.
• Increased histamine increases norepinephrine production and secretion.

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