Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU
A 65-year-old female is referred to the allergy clinic for evaluation of a rash, recently diagnosed as Indolent systemic mastocytosis (ISM). No history of asthma, allergic rhinitis, food allergy, atopic dermatitis or insect venom allergy.
She first noted the rash 10 years ago, affecting her torso and lower extremities, above the knee. The lesions were purple, 0.5 x 0.5 cm, multiple, nonpruritic, some were slightly raised. Two years ago, a dermatologist suspected a blood condition and she was referred a hematologist. Serum tryptase was elevated at 40 and a bone marrow biopsy confirmed systemic mastocytosis. Apart from the rash, she continues to be asymptomatic. EpiPen was prescribed. She takes an ACEI and beta-blocker for hypertension. She also takes cetirizine 10 mg po daily.
Past Medical History: Hypertension.
Current Medications: cetirizine 10 mg Oral tab, lisinopril 10 mg Oral tab tablet, metoprolol-XL 25 mg Oral Tb24 extended-release tablet.
Drug allergies: NKDA.
Family Medical History: Not contributory.
Physical Examination: Skin: rash affecting torso and lower extremities, above the knee. The lesions are slightly purple, 0.5 x 0.5 cm, multiple, nonpruritic, some are slightly raised. The rest of the examination is unremarkable.
What is the most likely diagnosis?
Indolent systemic mastocytosis (ISM). The patients has no symptoms. ISM progresses slowly or not at all and most patients have normal life expectancy.
What management would you recommend?
- Continue H1 antihistamine, cetirizine 10 mg po qpm
- if there are GI symptoms, add Pepcid 20 mg po bid
Any high risk medications that should be avoided?
- ACEI and beta-blocker decrease the efficacy of epinephrine (if given in emergency). A change from ACEI and beta-blocker to calcium channel blocker and/or diuretic was recommended to control blood pressure.
- high risk medications should be avoided or used with caution. Potentially problematic medications include the following:
Opioid analgesics, such as morphine and codeine
Vancomycin
Aspirin and other nonsteroidal antiinflammatory agents (NSAIDs) including ketorolac
Radiocontrast agents
Certain muscle relaxants and general anesthetics (succinylcholine, D-tubocurarine, metocurine, doxacurium atracurium, mivacurium, and rocuronium are more likely to cause a reaction than non-depolarizing muscle relaxants)
Does she need epinephrine autoinjector?
- use of epinephrine autoinjector (Auvi-Q 0.3 or EpiPen) in case there is life-threatening angioedema or anaphylactic episodes. Decrease risk of insect stings (she has no history of reactions after insect/bee stings). Have epinephrine autoinjector available.
What are the triggers of anaphylactic reaction in mastocytosis?
Trigger avoidance includes: exposure to heat, cold, acute emotional stress, very strenuous exercise, alcohol, spicy food, infections, vaccinations (potential trigger), anesthesia, surgery, and endoscopic procedures. Insect stings can precipitate symptoms in patients with mastocytosis, even when there is no IgE-mediated venom allergy detectable by skin or blood testing.
Any follow-up tests and consultations?
Evaluation by a hematologist with interest in mastocytosis is recommended
- In patients whose physical exam is unremarkable and weight is stable, the following yearly assessment is suggested:
Serum tryptase levels, which reflect mast cell burden.
Complete blood count with differential to monitor for changes in leukocytes, platelets, and eosinophils, as well as abnormal forms, since advanced forms of SM can be associated with other hematologic malignancies.
Serum chemistry panel to monitor for liver involvement and electrolyte imbalances.
Yearly bone densitometry for patients with documented osteopenia or osteoporosis
References
Treatment and prognosis of systemic mastocytosis. Mariana C Castells, MD, PhD and Cem Akin, MD, PhD. UpToDate, 2014. http://buff.ly/1lLOT6X
Patient information - Mastocytosis - NIH http://buff.ly/SfwC9n
Published: 03-26-2013
Updated: 05-26-2014
Showing posts with label Mastocytosis. Show all posts
Showing posts with label Mastocytosis. Show all posts
Systemic mastocytosis
Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU
A prevalence of mastocytosis of 1 in 10000 inhabitants has been reported, but underdiagnosis is assumed http://buff.ly/1ntpFM3. Mastocytosis may be the underlying diagnosis in a considerable subset of patients with recurrent “idiopathic anaphylaxis” http://buff.ly/Qj4Nw2.
Pathogenesis
Systemic mastocytosis is characterized by clonal expansion of mast cells, and most patients present with a genetic mutation in the stem cell factor receptor (KIT) gene. KIT or C-kit receptor is also called CD117. KIT is cytokine receptor expressed on the cell surface. KIT receptors binds to stem cell factors which causes certain types of cells to grow.
Some patients present with eosinophilia and symptoms may overlap with the hypereosinophilic syndrome.
Diagnosis
Serum tryptase level differentiate systemic mastocytosis from anaphylaxis. Bone marrow biopys is needed for definitive diagnosis.
Treatment
Treatment options for systemic mastocytosis include:
- H1- and H2-histamine-receptor blockade (e.g., cetirizine and ranitidine)
- oral disodium cromoglycate blocks the release of mediators from mast cells
- leukotriene-receptor blockade (montelukast)
- inhibition of PGD2 generation with acetylsalicylic acid (aspirin)
- proton-pump inhibitor (PPI) (e.g., omeprazole)
Oral cromolyn sodium in the management of systemic mastocytosis
A multicenter, double-blind, placebo-controlled trial of the efficacy of oral cromolyn sodium (200 mg orally four times per day) was conducted in 11 patients with systemic mastocytosis who had been maintained with the drug on an individualized compassionate-need basis. When the symptom scores were analyzed for gastrointestinal manifestations of disease (diarrhea, abdominal pain, nausea, and vomiting), cromolyn sodium treatment was significantly beneficial relative to placebo (p less than 0.02), whereas the benefit for nongastrointestinal manifestations did not reach statistical significance.
Oral cromolyn sodium is FDA-approved for management of systemic mastocytosis.
References
Cromolyn sodium in the management of systemic mastocytosis. Horan RF, Sheffer AL, Austen KF. J Allergy Clin Immunol. 1990 May;85(5):852-5.
http://www.ncbi.nlm.nih.gov/pubmed/2110198
Advances in basic and clinical immunology in 2007. Journal of Allergy and Clinical Immunology - Volume 122, Issue 1 (July 2008).
Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis http://goo.gl/vlQhm
Mastocytosis. NEJM blog, 2011.
Mastocytosis - Where are we now? World Allergy Organization summary, 2012.
Proposed diagnostic algorithm for patients with suspected mastocytosis. Allergy, 2014 http://buff.ly/1hZ4ayz
Systemic mastocytosis - Mayo Clinic video:
Pierre Noel, M.D., hematologist at Mayo Clinic in Arizona, discusses the diagnosis and treatment of systemic mastocytosis or mast cell disease.
Mast Cell Disorders (presentation on Google drive):
Published: 02/12/2009
Updated: 02/03/2012
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU
A prevalence of mastocytosis of 1 in 10000 inhabitants has been reported, but underdiagnosis is assumed http://buff.ly/1ntpFM3. Mastocytosis may be the underlying diagnosis in a considerable subset of patients with recurrent “idiopathic anaphylaxis” http://buff.ly/Qj4Nw2.
Pathogenesis
Systemic mastocytosis is characterized by clonal expansion of mast cells, and most patients present with a genetic mutation in the stem cell factor receptor (KIT) gene. KIT or C-kit receptor is also called CD117. KIT is cytokine receptor expressed on the cell surface. KIT receptors binds to stem cell factors which causes certain types of cells to grow.
Some patients present with eosinophilia and symptoms may overlap with the hypereosinophilic syndrome.
Diagnosis
Serum tryptase level differentiate systemic mastocytosis from anaphylaxis. Bone marrow biopys is needed for definitive diagnosis.
Treatment
Treatment options for systemic mastocytosis include:
- H1- and H2-histamine-receptor blockade (e.g., cetirizine and ranitidine)
- oral disodium cromoglycate blocks the release of mediators from mast cells
- leukotriene-receptor blockade (montelukast)
- inhibition of PGD2 generation with acetylsalicylic acid (aspirin)
- proton-pump inhibitor (PPI) (e.g., omeprazole)
Oral cromolyn sodium in the management of systemic mastocytosis
A multicenter, double-blind, placebo-controlled trial of the efficacy of oral cromolyn sodium (200 mg orally four times per day) was conducted in 11 patients with systemic mastocytosis who had been maintained with the drug on an individualized compassionate-need basis. When the symptom scores were analyzed for gastrointestinal manifestations of disease (diarrhea, abdominal pain, nausea, and vomiting), cromolyn sodium treatment was significantly beneficial relative to placebo (p less than 0.02), whereas the benefit for nongastrointestinal manifestations did not reach statistical significance.
Oral cromolyn sodium is FDA-approved for management of systemic mastocytosis.
References
Cromolyn sodium in the management of systemic mastocytosis. Horan RF, Sheffer AL, Austen KF. J Allergy Clin Immunol. 1990 May;85(5):852-5.
http://www.ncbi.nlm.nih.gov/pubmed/2110198
Advances in basic and clinical immunology in 2007. Journal of Allergy and Clinical Immunology - Volume 122, Issue 1 (July 2008).
Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis http://goo.gl/vlQhm
Mastocytosis. NEJM blog, 2011.
Mastocytosis - Where are we now? World Allergy Organization summary, 2012.
Proposed diagnostic algorithm for patients with suspected mastocytosis. Allergy, 2014 http://buff.ly/1hZ4ayz
Systemic mastocytosis - Mayo Clinic video:
Pierre Noel, M.D., hematologist at Mayo Clinic in Arizona, discusses the diagnosis and treatment of systemic mastocytosis or mast cell disease.
Mast Cell Disorders (presentation on Google drive):
Published: 02/12/2009
Updated: 02/03/2012
Mast Cells and Basophils
Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist
Role of mast cells in allergy had remained undetermined until the discovery of IgE in 1966. Then, IgE purified from many Liters of plasma, which had been donated from a patient with fatal myeloma, was distributed to researchers all over the world (http://buff.ly/12sD3cO).
Mast cells and basophils are the major cells in the early phases of immediate hypersensitivity reactions. Mast cells are fixed in the tissues while basophils circulate in the blood. Both are derived from CD34+ bone marrow progenitor cells.
CD differentiation (captions in German). Image source: Wikipedia.
Blood cell lineage. Image source: Wikipedia.
Mast cells (mind map).
Mast cells are derived from Kit+ (CD117), CD34+ stem cells in the bone marrow.Cell Morphology and Subpopulations
Mast cells are fixed in tissues and are bigger than basophils. They are 10 μm in size and have round nuclei. Mast cells have many more granules (1000 per cell) than basophils (80 granules) but their granules are 6 times smaller (0.2 µm vs. 1.2 µm).
Mast cells are subdivided into 2 types based on proteinase content:
TC mast cells - Tryptase and Chymase in granules, Kit+/CD88+
T mast cells - Tryptase only granules, Kit+/CD88-
TC
Tryptase/Chymase, Kit+/CD88+
T
Tryptase only, Kit+/CD88-
D
Dermis
Dual granules - Tryptase/Chymase
Dual surface markers - Kit+/CD88+
M
Mast cells
Major cell (10 µm) -- 2 times bigger than basophils (5 µm)
Minute granules (0.2 µm)
More granules (1000) than basophils (80)
Monophorm (round) nucleus
B
Basophils
Blood circulation
Bigger granules (1.2 µm)
Bilobar nucleus
Mast-Cell Signaling and Degranulation
Mast cells have FcεRI receptors which bind specific IgE. When a multivalent allergen binds to IgE, this leads to crosslinking of FcεRI receptors. Crosslinking, via signaling, leads to mast cell degranulation and production of cytokines, chemokines, and other mediators.
Role of IgE and mast cells in allergy. Image source: Wikipedia.
Mast Cell Mediators
The mediators fall into 3 groups remembered by the mnemonic ONC.
ONC:
Old
New
Cytokines
Old (pre-formed) Mediators in Granules of Mast Cells
Histamine is the classic example of a granule-associated mediator. Serine proteases (Tryptase/Chymase) are also pre-formed mediators in the granules of mast cells. The participate in airway remodelling in asthma.
Histamine structure. Image source: Wikipedia.
Structure of trypsin, a typical serine protease. Image source: Wikipedia.
Hereditary angioedema (HAE) is an autosomal dominant condition associated with episodic attacks of nonpitting edema. Patients with HAE have low levels of C1 inhibitor (a serine protease inhibitor).
Newly-generated Cell Mediators
Mast cells quickly generate different mediators from the metabolism of arachidonic acid: leukotrienes and prostaglandins (LTC4, LTB4, PGD2). These substances are produced within minutes of IgE-receptor crosslinking on the surface of mast cells.
Eicosanoids are signaling molecules made by oxygenation of 20-carbon essential fatty acids. There are 4 families of eicosanoids (PP-LT): prostaglandins (PG), prostacyclins (PGI), leukotrienes (LT) and thromboxanes (TX).
Arachidonic acid. Image source: Wikipedia.
LTC4 is a cysteinyl leukotriene, as are D4 and E4. Image source: Wikipedia.
LTB4. Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4. Image source: Wikipedia.
Prostaglandin D2. Image source: Wikipedia.
Leukotriene receptors mnemonic
Leukotriene
B4
BLT 1, 2 receptors
Leukotriene
C4, D4, E4
CysLT 1, 2 receptors
Cytokines
Different cytokines are produced by mast cells including interleukins, TNF, FGF, GM-CSF.
Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been implicated in the airway pathology in asthma. TNF-α may play an important role in severe refractory asthma unresponsive to inhaled CS.
Etanercept (Enbrel) is a recombinant human TNF-α receptor fusion protein (anti-TNF-α). Its therapeutic potential is based on the fact that TNF-alpha is the "master regulator" of the inflammatory response in many organ systems.
Mediators released from mast cells
Preformed mediators (from the granules):
- serine proteases, such as tryptase
- histamine (2-5 pg/cell)
- serotonin
- proteoglycans, mainly heparin (active as anticoagulant)
- TNF
Mature tryptase (β-tryptase)
Both α- and β-tryptase are elevated in mastocytosis.
Only β-tryptase (mature tryptase) is elevated in anaphylaxis.
Newly formed mediators:
- prostaglandin D2 (PGD2, eicosanoid)
- leukotriene C4 (LTC4, eicosanoid)
- platelet-activating factor (PAF)
- cytokines, e.g. IL-4
- eosinophil chemotactic factor
Mast cells, described in 1878, play a multifunctional role in the immune system, including in male infertility. Antihistamines may be used to treat male infertility due to the suspected role of mast cells (Medscape, 2011).
References
Allergy and Immunology MKSAP, 3rd edition.
Targeting TNF-α: A novel therapeutic approach for asthma. JACI, Volume 121, Issue 1, Pages 5-10 (January 2008)
Related Reading
FIT Corner Q & A from 5th edition of Cellular and Molecular Immunology, edited by Abul K. Abbas and Andrew H. Lichtman. ACAAI, 2004.
Mast Cell Disorders (presentation on Google drive):
Published: 12/13/2010
Updated: 11/12/2012
Reviewer: S. Randhawa, M.D., Allergist/Immunologist
Role of mast cells in allergy had remained undetermined until the discovery of IgE in 1966. Then, IgE purified from many Liters of plasma, which had been donated from a patient with fatal myeloma, was distributed to researchers all over the world (http://buff.ly/12sD3cO).
Mast cells and basophils are the major cells in the early phases of immediate hypersensitivity reactions. Mast cells are fixed in the tissues while basophils circulate in the blood. Both are derived from CD34+ bone marrow progenitor cells.
CD differentiation (captions in German). Image source: Wikipedia.
Blood cell lineage. Image source: Wikipedia.
Mast cells (mind map).
Mast cells are derived from Kit+ (CD117), CD34+ stem cells in the bone marrow.
Mast cells are fixed in tissues and are bigger than basophils. They are 10 μm in size and have round nuclei. Mast cells have many more granules (1000 per cell) than basophils (80 granules) but their granules are 6 times smaller (0.2 µm vs. 1.2 µm).
Mast cells are subdivided into 2 types based on proteinase content:
TC mast cells - Tryptase and Chymase in granules, Kit+/CD88+
T mast cells - Tryptase only granules, Kit+/CD88-
TC
Tryptase/Chymase, Kit+/CD88+
T
Tryptase only, Kit+/CD88-
D
Dermis
Dual granules - Tryptase/Chymase
Dual surface markers - Kit+/CD88+
M
Mast cells
Major cell (10 µm) -- 2 times bigger than basophils (5 µm)
Minute granules (0.2 µm)
More granules (1000) than basophils (80)
Monophorm (round) nucleus
B
Basophils
Blood circulation
Bigger granules (1.2 µm)
Bilobar nucleus
Mast-Cell Signaling and Degranulation
Mast cells have FcεRI receptors which bind specific IgE. When a multivalent allergen binds to IgE, this leads to crosslinking of FcεRI receptors. Crosslinking, via signaling, leads to mast cell degranulation and production of cytokines, chemokines, and other mediators.
Role of IgE and mast cells in allergy. Image source: Wikipedia.
Mast Cell Mediators
The mediators fall into 3 groups remembered by the mnemonic ONC.
ONC:
Old
New
Cytokines
Old (pre-formed) Mediators in Granules of Mast Cells
Histamine is the classic example of a granule-associated mediator. Serine proteases (Tryptase/Chymase) are also pre-formed mediators in the granules of mast cells. The participate in airway remodelling in asthma.
Histamine structure. Image source: Wikipedia.
The seminal work on histamine was published in 1910, but histamine was not identified as a mediator of anaphylactic reactions until 1932. Histamine is a major mediator responsible for the symptoms of allergic rhinitis, with its activities mediated through 4 G protein-coupled receptors. Most of histamine's effects are exerted through the H₁ receptor, but some effects are through the H₂ and H₃ receptors, and possibly also through the H₄ receptor (source: The basics of histamine biology. Lieberman P. Ann Allergy Asthma Immunol. 2011 Feb;106(2 Suppl):S2-5. Epub 2010 Sep 16.)
Structure of trypsin, a typical serine protease. Image source: Wikipedia.
Hereditary angioedema (HAE) is an autosomal dominant condition associated with episodic attacks of nonpitting edema. Patients with HAE have low levels of C1 inhibitor (a serine protease inhibitor).
Mast cells quickly generate different mediators from the metabolism of arachidonic acid: leukotrienes and prostaglandins (LTC4, LTB4, PGD2). These substances are produced within minutes of IgE-receptor crosslinking on the surface of mast cells.
Eicosanoids are signaling molecules made by oxygenation of 20-carbon essential fatty acids. There are 4 families of eicosanoids (PP-LT): prostaglandins (PG), prostacyclins (PGI), leukotrienes (LT) and thromboxanes (TX).
Arachidonic acid. Image source: Wikipedia.
LTC4 is a cysteinyl leukotriene, as are D4 and E4. Image source: Wikipedia.
LTB4. Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4. Image source: Wikipedia.
Prostaglandin D2. Image source: Wikipedia.
Leukotriene receptors mnemonic
Leukotriene
B4
BLT 1, 2 receptors
Leukotriene
C4, D4, E4
CysLT 1, 2 receptors
Cytokines
Different cytokines are produced by mast cells including interleukins, TNF, FGF, GM-CSF.
Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been implicated in the airway pathology in asthma. TNF-α may play an important role in severe refractory asthma unresponsive to inhaled CS.
Etanercept (Enbrel) is a recombinant human TNF-α receptor fusion protein (anti-TNF-α). Its therapeutic potential is based on the fact that TNF-alpha is the "master regulator" of the inflammatory response in many organ systems.
Mediators released from mast cells
Preformed mediators (from the granules):
- serine proteases, such as tryptase
- histamine (2-5 pg/cell)
- serotonin
- proteoglycans, mainly heparin (active as anticoagulant)
- TNF
Mature tryptase (β-tryptase)
Both α- and β-tryptase are elevated in mastocytosis.
Only β-tryptase (mature tryptase) is elevated in anaphylaxis.
Newly formed mediators:
- prostaglandin D2 (PGD2, eicosanoid)
- leukotriene C4 (LTC4, eicosanoid)
- platelet-activating factor (PAF)
- cytokines, e.g. IL-4
- eosinophil chemotactic factor
Mast cells, described in 1878, play a multifunctional role in the immune system, including in male infertility. Antihistamines may be used to treat male infertility due to the suspected role of mast cells (Medscape, 2011).
References
Allergy and Immunology MKSAP, 3rd edition.
Targeting TNF-α: A novel therapeutic approach for asthma. JACI, Volume 121, Issue 1, Pages 5-10 (January 2008)
Related Reading
FIT Corner Q & A from 5th edition of Cellular and Molecular Immunology, edited by Abul K. Abbas and Andrew H. Lichtman. ACAAI, 2004.
Mast Cell Disorders (presentation on Google drive):
Published: 12/13/2010
Updated: 11/12/2012
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