Glossary of mast cell related terms: P-Z

Parasympathetic nervous system: Part of the autonomic nervous system.  Regulates digestion and other functions.

Prostaglandin D2 (PGD2): The dominant prostaglandin produced by mast cells.

9a,11b-PGF2: a breakdown product of prostaglandin D2; can be measured to assess level of mast cell activation

Platelet activating factor (PAF): a mast cell mediator that correlates with severity of anaphylaxis; induces degranulation and release of leukotrienes and prostaglandins

Postural orthostatic tachycardia (POTS): increase of 30 bpm or more when standing in the absence of orthostatic hypotension.

Premedication: taking medication in advance of an event in order to suppress an undesirable reaction during the event, such as premedicating before surgery

Pre-stored: as relates to mast cell biology, mediators that are made inside the cell and stored in granules to be released at a later time

Progenitor cell: a cell that develops into another type of cell

Proliferation: growth and expansion of a cell population

Prostaglandin: a type of eicosanoid with wide ranging biological effects; PGD2 is the prostaglandin most abundantly produced by mast cells

Protracted anaphylaxis: a long episode of anaphylaxis symptoms despite treatment

Rare disease: a disease that affects only a small amount of people in a population; in the US, defined as affecting 200,000 people or less in the US

Rebound: a resurgence of symptoms after quelling symptoms earlier

Receptor: a protein on the outside of cells that bind specific molecules, causing a specific action to occur

Secretion: the release of molecules from inside the cell to the outside environment without degranulation

Sensitization: production of IgE specific to an allergen without obvious allergic reaction to the allergen

Serotonin: a neurotransmitter released by a number of cell types, including mast cells

Smouldering systemic mastocytosis (SSM): a form of SM in which organ damage and failure could eventually occur; diagnosed when someone with SM has two or more B findings

Splenomegaly: swelling of the spleen

Stem cell factor (SCF): a mast cell growth factor; SCF binds to CKIT and tells mast cells to stay alive and make more mast cells

Sympathetic nervous system: Part of the autonomic nervous system.  Controls the fight or flight response

Systemic mastocytosis (SM): a proliferative mast cell disease in which too many mast cells are produced

Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): co-occurrence of SM with another proliferative blood cell disorder, such as essential thrombocythemia or chronic myelogenous leukemia

Tachycardia: rapid heartbeat

Third spacing: when fluid is forced out of a place the body can use it and becomes trapped, such as ascites or angioedema

TLR: toll like receptor; receptors on the outside of many cells (including mast cells) that activate immune response to infections

Telangiectasia macularis eruptive perstans (TMEP): a less common form of cutaneous mastocytosis.  Found almost exclusively in adults.

Tryptase: a mast cell mediator; when tested outside of a symptomatic episode, it is used to measure the baseline amount of mast cells present ; when tested during a symptomatic episode, it can be used to identify mast cell activation

Urticaria pigmentosa (UP): also called maculopapular cutaneous mastocytosis (MPCM).  The most common form of cutaneous mastocytosis.

Urticaria: hives

Wheal and flare response: a reaction marked by redness and raised, taut skin due to histamine release

Glossary of mast cell related terms: M-O

Mast cell: white blood cells with important roles in allergy, anaphylaxis and immune defense that live in tissues and only briefly circulate in the blood; also called mastocytes

Mast cell activation: a change in mast cell behavior that occurs following exposure to a trigger that may indicate allergy or infection; a state in which mast cells release mediators, both through degranulation and through secretion; in some instances, culminating in anaphylaxis

Mast cell disease: a disease that occurs due to fundamental error in mast cell proliferation or activation physiology

Mast cell disorder: used synonymously with mast cell disease

Mast cell leukemia: a very aggressive mast cell disease marked by massively excessive proliferation of mast cells, culminating in progressive organ failure

Mast cell sarcoma: a very aggressive mast cell disease that presents as a connective tissue tumor and progresses to mast cell leukemia

Mast cell stabilizer: a medication that decreases the likelihood of mast cell degranulation and mediator release

Mastocytic enterocolitis: the phenomenon of having too many mast cells in the GI tract; originally described as more than 20 mast cells/ high power field, but there is no consensus on how many mast cells in a field is too many

Mastocytoma: a benign mast cell tumor. Most frequently occurs on skin, but can occur elsewhere in the body.

Mast cell activation disease (MCAD): usually a catchall term for mast cell diseases, although some people exclude cutaneous mastocytosis from this category

Mast cell activation disorder (MCAD): an alternate term for mast cell activation syndrome (MCAS); a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators

Mast cell activation syndrome (MCAS): a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators; occurs secondary to a known condition or idiopathically, in which no primary condition is identified; “primary” mast cell activation syndrome has its own name, MMAS

Mediator: a molecule released from a cell that has effects on the environment outside the cell; mast cells release dozens of mediators

Monoclonal mast cell activation syndrome (MMAS) : a mast cell disease diagnosed when a patient meets some criteria for SM but not enough for an SM diagnosed

Monophasic anaphylaxis: an anaphylactic event in which symptoms resolve following administration of medication and do not recur at a later time

Mutation: a change in the genetic sequence that can affect the way a gene is expressed, or in the way its gene product is made or functions

Myeloid: concerning cells that develop into granulocytes, monocytes, platelets or erythrocytes

Myeloproliferative neoplasm: a disorder caused by aberrant proliferation of a myeloid cell line, such as SM, myelofibrosis, essential thrombocythemia or polycythemia vera, among others

Neoplasm: an abnormal cell

N-methylhistamine: a breakdown product of histamine; can be tested for to assess mast cell activation

Oral allergy syndrome: An IgE reaction to raw fruits and vegetables that causes itching and swelling in the mouth and throat.

Orthostatic hypotension (OH): 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.

Orthostatic intolerance (OI): symptoms that occur when transitioning to a standing position

Glossary of mast cell related terms: F-L

FceRI: the high affinity IgE receptor; where IgE molecules bind to the outside of cells, like mast cells; binding the FceRI receptor triggers mast cell activation

Food associated, exercise induced anaphylaxis: An IgE mediated reaction that is triggered by ingesting certain foods in close time proximity to exercise

Food protein induced enterocolitis syndrome (FPIES): An allergic reaction to food proteins that is not mediated by IgE, usually found in infants; the most severe non-IgE mediated food hypersensitivity

Gastroparesis: a condition in which stomach contents are not emptied into the small intestine within an appropriate time period without an obvious anatomical explanation

Granule: a pocket inside a cell that holds molecules to be released outside of the cell

Granulocyte: white blood cells that have granules inside the cells that hold molecules to be released outside of the cell; mast cells, eosinophils, basophils and neutrophils are granulocytes

H1: histamine 1 receptor

H1 inverse agonist: a class of drugs that interferes with the effect of histamine at the H1 receptor

H2: histamine 2 receptor

H2 blocker: a class of drugs that interferes with the effect of histamine at the H2 receptor

Heparin: a mast cell mediator; a blood thinner

Hepatomegaly: swelling of the liver

Hepatosplenomegaly: swelling of the liver and spleen

Hereditary angioedema (HAE): a heritable blood disorder that causes episodes of protracted swelling that can be life threatening.

Histamine: a neurotransmitter; responsible for a large portion of symptoms seen in mast cell disease and anaphylaxis

HPA axis: the signals and feedback loops that regulate the activities of the hypothalamus, pituitary gland and adrenal glands to coordinate the body’s stress response; also helps regulate digestion, immune activation, sexuality and energy metabolism

Hypersensitivity: allergic reaction

Hypersplenism: overactivity of the spleen

IgE: an antibody that triggers allergic responses

Kounis Syndrome: an event in which a patient experiences severe chest pain or heart attack as the result of an allergic reaction; also called allergic angina or allergic myocardial infarction

Late onset anaphylaxis: Anaphylaxis that begins several hours after exposure to trigger

Leukotrienes: Structural class related to prostaglandins produced by the enzyme 5-lipoxygenase (5-LO); mediators released by mast cells.

Leukotriene receptor antagonist: A class of drugs that interferes with the function of leukotrienes; examples include montelukast and zafirlukast.

Ligand: a molecule that binds to another molecule, triggering a specific effect; with regards to mast cell disease, ligands bind to receptors, such as IgE (ligand) binding to FceRI (receptor)

LO: lipoxygenase; the enzyme that produces leukotrienes

Low histamine diet: a diet which minimizes dietary sources of histamine, which can help reduce symptoms for some mast cell patients; there is no authoritative list of low histamine foods and some trial and error is required

 

Glossary of mast cell related terms: A-E

Allergic march: the progressive accumulation of atopic conditions beginning in the first year of life; usually atopic dermatitis, allergic rhinitis, asthma, food allergy

Anaphylaxis: a rapidly progressing allergic reaction that involves multiple organ systems; can be fatal

Angioedema: Swelling caused when fluid leaves the bloodstream and becomes trapped between the deep dermis and subcutaneous tissue.

Anticholinergic: blocking the molecule acetylcholine from sending signals in the nervous system.  Many medications are anticholinergic, which can cause many side effects.

Ascites: free fluid in the abdomen; a form of third spacing

Aggressive systemic mastocytosis (ASM): a form of systemic mastocytosis in which mast cells invade organs, causing damage and dysfunction; diagnosed when a person meeting the criteria for SM has one or more C finding, criteria that indicate organ damage caused by mast cells

Asthma: inflammation of the airways causing swelling, narrowing and extra mucus production; can be allergic in nature

Atopy: tendency of a person to develop allergic diseases like asthma

Autoimmune disease: a disease caused when the immune system attacks healthy cells; mast cell diseases are not autoimmune diseases

Autonomic nervous system: a part of the nervous system that controls many involuntary functions of the body, including digestion.  It is composed of both the parasympathetic nervous system and the sympathetic nervous system.

B finding: criteria that indicate SM is progressing towards mast cells invading organs and damaging them; if 2 or more are present, smouldering systemic mastocytosis (SSM) is diagnosed

Biphasic anaphylaxis: Second episode of anaphylaxis symptoms after resolution

Bradykinin: a mediator released by mast cells that causes inflammation, pain and swelling

CD117: another name for CKIT receptor, found normally on the outside of mast cells

CD2: a marker not usually found on the outside of mast cells; an indicator of systemic mastocytosis; a cell adhesion molecule

CD25: a marker not usually found on the outside of mast cells; an indicator of systemic mastocytosis; part of a receptor for IL-2

CD34: a marker normally found on the outside of cells that become mast cells, and on new mast cells

Chronic urticaria: hives lasting longer than six weeks; can include angioedema

Circadian rhythm: the body’s internal clock

CKIT: a receptor on the outside of mast cells that binds stem cell factor, telling mast cells to stay alive and make more cells; is often mutated in systemic mastocytosis

Complement : a system of many small proteins circulating in the blood that can attack infectious agent ; can also cause angioedema

Cortisol : a steroid hormone produced by the adrenal glands ; critical in regulating stress response

COX : cyclooxygenase; enzymes that produce prostaglandins

Cutaneous mastocytosis (CM): infiltration of the skin by excessive mast cells.  The most common type of mastocytosis.

D816V/CKIT+: a specific mutation at codon 816 of the CKIT gene that causes the CKIT receptor to be misshapen so that mast cells get inappropriate signals to stay alive and keep making more cells

Darier’s sign: a wheal and flare response elicited by touching mast cell lesions; caused by histamine release

Desensitization: the elimination of the body’s allergic response to something

Diffuse cutaneous mastocytosis (DCM): The most severe presentation of cutaneous mastocytosis.  Lesions cover much of the body and may blister or bleed.

Deconditioning: when the body becomes acclimated to less physical stress and becomes less able to function properly under normal conditions.

Degranulation: the release of mediators stored in granules inside a cell; mast cell degranulation contributes to immune response as well as symptom profile in mast cell disease and anaphylaxis

Delayed food-induced anaphylaxis to meat: An IgE mediated reaction to beef, pork or lamb that occurs several hours after eating; caused by a tick bite inducing production of antibodies to carbohydrate a-gal.

Dysautonomia: fundamental dysfunction of the autonomic nervous system; there are many types, including POTS

Ehlers-Danlos Syndrome (EDS): a group of conditions caused by hypermobility and/or known genetic mutation affecting production of connective tissue components; Hypermobility EDS is seen disproportionately in the mast cell community

Edema: swelling; excess fluid trapped in tissues

Eicosanoid: the molecular class that includes prostaglandins and leukotrienes

Eosinophilia: elevation of eosinophils in the blood

Eosinophilic esophagitis: infiltration of the esophagus by eosinophils

Eosinophilic GI disease: IgE and delayed cell mediated reactions to foods caused by overactive eosinophils, affecting the GI tract.

Eosinophils: a granulocyte functioning similar to mast cells; mast cells and eosinophils can activate each other

Epinephrine: a hormone used to treat anaphylaxis

Exercise intolerance: diminished ability or inability to perform physical exercise; can be caused by a number of medical conditions

Naturally occurring mast cell stabilizers: Part 4

I mentioned resveratrol in the previous post under its broad classification as a phenol.  Looking more narrowly, resveratrol is a derivative of stilbene.  It is found in several foods, including grapes and berries like blueberries and raspberries.  Resveratrol can form oligomers, in which several of the same molecule are connected together.  One such oligomer is Gnetin H.  This product is isolated from Paeonia anomala and is used in Mongolian Chinese medicine.  It has been found to significantly impair mast cell degranulation and is effective at lower doses than resveratrol.  Gnetin H also decreased histamine secretion and production of TNF and IL-4, as well as COX-2 and PGE2 (not a typo, prostaglandin E2).

Polydatin is a precursor to resveratrol.  In a rat model, administration of polydatin was found to make the small intestine mucosa much less “leaky”.  It also inhibited hypersensitivity in the small intestine.  Importantly, it decreased degranulation by as much as 65% (determined by examining tissue with toluidine blue staining), and decreased histamine in both serum and intestinal mucosa.  Degranulation involves changes in calcium inside the mast cell and treatment with polydatin interfered with this process.  It also interrupted production of IgE by suppressing IL-4 secretion.  In another paper, polydatin was also found to suppress anaphylaxis in the mouse model of passive cutaneous anaphylaxis.

Hydroxytyrosol is a phenol derived from olive oil and olive leaves.  In nature, it occurs in the form of oleuropein, which can be broken down to hydroxytyrosol.  In a study that used β-hexosaminidase as a  marker for mast cell degranulation, both hydroxytyrosol and oleuropein inhibited activation in cells at high concentrations. This is promising but future research is needed.

In mouse and human mast cells, hypothemycin was found to interfere with activation of the CKIT receptor and the IgE receptor (FceRI).  This resulted in suppression of degranulation and production of cytokines, including IL-4.  This product was originally extracted from a mushroom of the Hypomyces genus.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Kim M, et al. Gnetin H isolated from Paeonia anomala inhibits FceRI-mediated mast cell signaling and degranulation. J Ethnopharmacol 2014 Jul 3; 154(3): 798-806.

Yang B, et al. Polydatin attenuated food allergy via store-operated calcium channels in mast cell. World J Gastroenterol 2013 Jul 7; 19(25): 3980-3989.

Yuan M, et al. Polydatin (PD) inhibits IgE-mediated passive cutaneous anaphylaxis in mice by stabilizing mast cells through modulating Ca2+ mobilization. Toxicol Appl Pharmacol 2012 Nov 1; 264(3): 462-469.

Persia FA, et al. Hydroxytyrosol and oleuropein of olive oil inhibit mast cell degranulation induced by immune and non-immune pathways.  Phytomedicine. 2014 Sept 25; 21(11): 1400-1405.

Naturally occurring mast cell stabilizers: Part 3

Coumarins are compounds that occur naturally in a number of plant species.  Several medications are derived from coumarins, including several anticoagulants, such as warfarin. They are notable for being fragrant.  Coumarin increases resorption of edema fluids.

Scopoletin is a coumarin present in the root structures of several species, including Urtica dioica (stinging nettle), Scopolia japonica (Japanese belladonna), chicory and passion flower.  In human mast cells, scopoletin interferes with production of TNF, IL-6 and IL-8.  It was found to inhibit NF-kB, which participates in the inflammatory response.

Artekeiskeanol A is a coumarin extracted from Artemisa keiskeana.  In traditional medicine systems, it is sometimes used to treat rheumatoid arthritis.  It suppressed degranulation, decreased production of TNF and IL-13.  Selinidin, a coumarin found in Angelica keiskei, suppresses IgE-initiated degranulation and decreases production of LTC4 and TNF. Rottlerin from the tree Mallotus philippensis attenuates IgE activation, degranulation of at least airway mast cells, and histamine release.

Cinnamic acid is a coumarin that decreased antigen stimulated degranulation in basophils, but similar action has not been recorded in mast cells.  It is most commonly extracted from cinnamon oil. A furanocoumarin found in Angelica dahurica inhibits action of COX-2 and 5-LO, decreasing production of PGD2 and LTC4, in addition to preventing degranulation.

Thunberginol A and B from Hydrangeae macrophylla inhibits histamine release from activated mast cells.  Thunberginol A prevents release of TNF and IL-4. In particular, thunberginol B is a potent mast cell stabilizer, suppressing degranulation from IgE or other causes.  It can also suppress production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF when triggered by IgE.

Ellagic acid is found in nuts and fruit, such as strawberries, raspberries, pomegranate and walnuts. It interferes with IgE activation of mast cells and decreases release of histamine, TNF and IL-6.

Plant phenols have been reported to have medicinal effects for many years.  Magnolol and honokiol, two substance found in the bark of Magnolia obovata, can interfere with basophil degranulation as well as allergic response more generally.  Resveratrol is a phenol derivative present in berries, peanuts and grapes.  It is a potent supporessor of inflammatory mast cell products, including TNF, IL-6 and IL-8.  It also interferes with the structures required for degranulation and can also interfere with basophil degranulation.

Curcumin is another phenol derivative and is already quite popular in the mast cell community. (Disclaimer: I take turmeric, which contains curcumin.)  Curcumin has well described anti-inflammatory and anti-allergic benefits.  It inhibits mast cell and basophil degranulation and decreases release of IL-4 and TNF.  It also suppresses a popular lab model of allergy, passive cutaneous anaphylaxis.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Moon PD, et al. Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkappaB/NF-kappaB signal cascade in the human mast cell line HMC-1. Eur J Pharmacol 2007 Jan 26; 555(2-3): 218-225.

Kishiro S, et al. Selinidin suppresses IgE-mediated mast cell activation by inhibiting multiple steps of Fc epsilonRI signaling. Biol Pharm Bull 2008 Mar; 31(3): 442-448.

Bheekha-Escura, Roy, et al. Pharmacologic regulation of histamine release by the human recombinant histamine-releasing factor. May 1999; 103(5): 937-943.

Hong J, et al. Suppression of the antigen-stimulated RBL-2H3 mast cell activation by Artekeiskeanol A. Planta Med 2009 Nov; 75(14): 1494-1498.

Naturally occurring mast cell stabilizers: Part 2

As discussed in the previous post, many flavonoids can modulate mast cell responses.  Luteolin, a flavone, has been studied for its powerful effects on inflammatory cells.  With prophylactic administration of this molecule, activation of mast cells and T cells can be prevented in a disease model for multiple sclerosis. Luteolin can also inhibit IgE-triggered degranulation as well as production of various mediators.  It is found in many foods, including celery, carrots, and chamomile tea.

Genistein, an isoflavone, prevents IgE-induced degranulation and histamine release.  It is a natural tyrosine kinase inhibitor, mostly activate against EGFR. It can be extracted from Genista tinctoria, also called dyer’s broom.  Several structurally related molecules also have mast cell modulating effects. Amentoflavone, from Ginkgo biloba and St. John’s Wort, decreases histamine release by mast cells. Ginkgetin, derived from Ginkgo biloba leaves, inhibits phospholipase A2, a mast cell mediator, and inhibits production of PGD2 by interfering with the COX-2 enzyme and of LTC4 by interfering with 5-lipoxygenase.

Emodin is an anthraquinone with a long history of use in herbal medicine traditions.  It boasts an array of anti-allergic activity and can inhibit the following IgE induced effects: mast cell degranulation; production of TNF, PGD2 and LTC4; and secretion of TNF and IL-6. It is under investigation for use in type II diabetes, where it can decrease the activity of glucocorticoids in obese animals and may treat insulin resistance.  Emodin can be found in rhubarb, frangula bark and other plants.

A number of other natural molecules also have mast cell stabilizing effects. Epigallocatechin gallate, found in higher quantities in white and green teas, as well as apples, onions and hazelnuts, can inhibit mast cell degranulation and LTC4 secretion.  Xanthones found in the juice and fruit of the purple mangosteen, Garcinia mangostana, decreased histamine release as well as PGD2, LTC4 and IL-6 from mast cells.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 2013 Oct-Dec; 27(4): 955-959.

Theoharides TC, Kempuraj D, Iliopoulou BP. Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Adv Exp Med Biol 2007; 601: 423-30.

Son JK, et al. Ginkgetin, a biflavone from Ginkgo biloba leaves, inhibits cyclooxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells. Biol Pharm Bull 2005 Dec; 28(12): 2181-4.

Lu Y, et al. Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochem Pharmacol 2011 Dec 1; 82(11): 1700-1708.

Kim DY, et al. Emodin attenuates A23187-induced mast cell degranulation and tumor necrosis factor-a secretion through protein kinase C and IkB kinase 2 signaling. Eur J Pharmacol 2014 Jan 15; 723: 501-506.

Naturally occurring mast cell stabilizers: Part 1

Warning: Naturally occurring molecules can interfere with medications or adversely affect disease state.  Please consult with your managing provider before adding supplements or drastically changing diet.

Flavonoid is a broad term used to describe certain plant derived metabolites. It can be used to refer to a variety of molecules, including isoflavonoids, neoflavonoids and anthoxanthins, which are categorized based on structure.  A number of flavonoids have been shown experimentally to modulate mast cell behavior and function as mast cell stabilizers.

Homoisoflavonone decreases production of PGD2 and leukotrienes B4 and C4 by downregulating COX-2 and 5-LO, the enzymes that make these molecules from arachidonic acid. It also interferes directly with the manufacture of IL-6 and TNF in mast cells stimulated by IgE (the traditional allergy pathway).  Homoisoflavonone can be isolated from bulbs of Cremastra appendiculata, which is commonly called Chinese tulip despite being an orchid.  Chinese tulip is commonly used in Chinese medicine.  Related homoisoflavonoids, extracted from the tuber of Ophiopogon japonicas, mondograss, are anti-inflammatories, possibly by interfering with COX-2 and 5-LO.

Flavonols have been noted for their anti-allergic activity for a number of years.  Morin is a flavonol found in natural sources like Maclura pomifera (Osage orange) and Psidium guajava (guava).  Morin prevents mast cell degranulation and manufacture of cytokines like TNF and IL-4, as well as suppressing IgE activation almost completely at higher doses (please note the study on this used mice so it’s not clear what those dose would be in humans).  Other mast cell active flavonols include quercetin, myricetin, rutin, fisein and kaempferol.

Quercetin downregulates the expression of histidine decarboxylase, the enzyme that modifies histidine, an amino acid, to histamine.  Quercetin also inhibits release of histamine, prostaglandins and leukotrienes.  Additionally, it decreases production and release of IL-1b, IL-6, IL-8 and TNF.  Quercetin was reported to be stronger and more effective at inhibiting mediator release than cromolyn when taken prophylactically, although this has not yet been judged as true by any regulatory body.  Quercetin is found naturally in a number of foods, such as red onion, sweet potato, kale, and many others.  It is also found in small quantities in teas made with Camellia sinensis.  Rutin is a derivative of quercetin, found in citrus fruits, apples, cranberries and others.

Fisetin, kaempferol, myricetin, quercetin and rutin inhibited IgE mediated histamine release and prevented increased concentration of calcium inside mast cells, which is necessary for degranulation.  Fisetin, quercetin and rutin all decreased production of IL-1b, IL-6, IL-8 and TNF. Fisetin, myricetin and rutin all decreased action of NF-kB, which controls the pathway regulating production of cytokines. Myricetin is a particularly effective mast cell stabilizer.  It decreased degranulation and release of TNF and IL-6, but not IL-1b or IL-8.

Flavonols have been evaluated for other medicinal properties aside from mast cell modulation.  Myricetin has been suggested as a treatment for many diseases, including diabetes, while kaempferol affects many molecular pathways, including estrogen signaling.  These molecules occur naturally in a number of plants, including walnuts, onions and red grapes for myricetin; apples, onions, persimmons, strawberries and cucumbers for fisetin; and potatoes, squash, cucumbers, peaches and Aloe vera for kaempferol.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Weng Z., et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity inhumans. PLoS One. 2012; 7(3): e33805.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Lee, YS, et al. Homoisoflavonone prevents mast cell activation and allergic responses by inhibition of Syk signaling pathway. Allergy 2014; 69: 453-462.

 

 

 

 

Role of sex hormones in hereditary angioedema

Sex hormones are well known for influencing symptoms of immune mediated conditions. Estrogen can affect cell proliferation and activation. Menses, pregnancy, menopause, and use of oral contraception are known to affect hereditary angioedema (HAE) but it is not yet clear how.

One hypothesis is that estrogen may activate the kallikrein-kinin system, thereby increasing production of bradykinin. Another hypothesis is that estrogen can affect the expression of the FXII gene, which produces the initiating molecule in the bradykinin pathway. Estrogen may also regulate the B2 receptors that bradykinin binds to. While all of these ideas are possible, there have not yet been any definitive findings.

In female patients, onset of HAE often correlates with the start of puberty. Menses, pregnancy and delivery also correlate with flare ups of HAE. Puberty makes HAE attacks more frequent and severe in 56.7% of cases; menses does the same in 35.3%; ovulation, 14%. Use of estroprogestin contraceptives irritate and worsen HAR in 63-80% of HAE women. The first trimester of pregnancy is known to be a difficult time for HAE women, as circulating estrogen is particularly high and many women discontinue maintenance therapy out of safety concerns for the fetus.

In patients with type III HAE in whom a Factor XII mutation has been identified, episodes occur almost exclusively during periods of high estrogen. This initial observation led to type III to be called “estrogen dependent HAE”, but this only refers to a subset of patients and has fallen out of use. Estrogen levels do not affect symptoms in other type III HAE patients (without the Factor XII mutation) and in many acquired angioedema patients.

Female HAE patients of reproductive age, who are not using oral contraceptives, often have polycystic or multifollicular ovaries. Ovulation is a complex multistep process in which two steps are controlled by C1INH.

 

 

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

Kaplan AP, et al. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010 Aug; 47(13):2161-9.

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

 

 

 

 

Gastroparesis: Idiopathic gastroparesis (Part Seven)

Gastroparesis occurring in the absence of any known trigger, such as diabetes, surgery, medication or disease related onset, is classified as idiopathic gastroparesis.  In most series that include patients with multiple forms of gastroparesis, idiopathic gastroparesis (IGP) is the most common, affecting 35-67% of GP cases.  As with most forms of GP, IGP affects about three times more women than men, particularly young and middle-aged women.  IGP in particular affects young women who are overweight or obese.

In a study including 243 patients with IGP, 88% were female.  34% reported frequent nausea, 23% abdominal pain and 19% vomiting.  28% had severely delayed gastric emptying, here defined as more than 35% retention of contents four hours after consumption.  46% were overweight.  When compared to patients with diabetic GP, IGP patients more often reported feeling too full after eating and that their hunger was sated by smaller meals.  IGP patients demonstrated more severe gastric retention than type I diabetic GP patients.

Moderate/severe upper abdominal pain was found to be more frequent in IGP, and correlated with GP severity, decrease in quality of life, depression and anxiety.  Having pain as the predominant symptom causes quality of life impairment equivalent with nausea and vomiting.

Bloating is a common GP symptom.  Severe bloating was present in 41% of patients, and was more common in overweight female patients.  It also corresponded with severe nausea, fullness, distention, abdominal pain and notable bowel dysfunction.  Quality of life and other measures of wellbeing decrease as bloating becomes more severe.

Idiopathic GP is treated similarly to other types, but diagnosis may be delayed due to the lack of a known trigger.  Medications that have been reported as helpful but have not been studied in larger populations include sildenafil, paroxetine, cisapride, tegaserod, clonidine and buspirone.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.