Mast Cell Disorders. Andrew M. Smith, MD, MS
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1 Mast Cell Disorders Andrew M. Smith, MD, MS Division of Immunology, Allergy, and Rheumatology University of Cincinnati and Cincinnati VA Medical Centers August 10 and 11, 2012
2 Disclosures None The contents do not represent the view of the Department of Veterans Affairs or U.S. Government
3 Objectives Identify the clinical features of mast cell disorders Explain the immunologic mechanisms of mast cell disorders Describe appropriate evaluation and treatment of mast cell disorders
4 Case Presentation 35 year old male, previously healthy Symptoms began in the winter of 2011 Woke up in the middle of the night Started with hands and feet itching Abdominal pain, diarrhea, and vomiting Lip swelling, quickly progresses to tongue swelling Presented to the Emergency Department Received epinephrine and steroids
5 Case Presentation Fall most severe episode Awaked in the early morning Hives head to toe, tongue and lip swelling Treated with loratidine, famotidine, and prednisone daily
6 Case Presentation Further episodes: 11 times in 12 months and 4 episodes in the past 14 days Facial/lip swelling with every episode Faster progression to respiratory distress and low blood pressure Most recent episodes with chest pain Most episodes have started in the middle of the night
7 Case Presentation Allergy/Immunology consulted What is causing the recurrent episodes of anaphylaxis? Definitions of anaphylaxis, angioedema, and urticaria
8 Anaphylaxis - Definition Difficulty in defining anaphylaxis Traditional Definition A systemic, immediate hypersensitivity reaction caused by immunoglobulin E (IgE)- mediated immunologic release of mediators from mast cells and basophils
9 Anaphylaxis World Allergy Organization definition: A severe, life threatening, generalized or systemic hypersensitivity reaction involving two or more organ systems Allergic anaphylaxis reaction mediated by an immunologic mechanism Non-allergic anaphylaxis non-immunologic reaction WAO Journal 2011; 4:13 37
10 Anaphylaxis - Symptoms Signs and Symptoms Cutaneous >90% Urticaria/Angio edema Percentage 85-90% Flushing 45-55% Respiratory 40-60% Dyspnea/Whe ezing 45-50% Rhinitis 15-20% Dizziness/Synco pe 30-35% Signs and Symptoms Percentage Hypotension 30-35% Abdominal 25-30% Nausea/Vomiti ng Diarrhea Miscellaneous Headache 5-8% Substernal pain 4-6% Seizure 1-2% J Allergy Clin Immunol 2010;126:
11 Angioedema - Definition Swelling in the deep skin tissue Fewer sensory nerve endings Little or no itch May be described as painful or burning Generally asymmetric and short lived May occur in isolation, accompanied by urticaria, or as a component of anaphylaxis Can be life-threatening Cleveland Clinic Journal of Medicine January 2009 vol
12 Angioedema - Locations Larynx Can develop rapidly Early symptoms: hoarse voice, throat tightness, and difficulty swallowing Skin and mucous membranes Mild pain and warmth may be present, burning sensation Resolves without leaving residual markings on the skin Bowel wall Colicky abdominal pain, sometimes nausea, vomiting and/or diarrhea Bowel wall edema often visualized by abdominal CT or ultrasound
13 Urticaria Hives Itchy, red raised lesions Turn pale when pressed, indicating the presence of enlarged blood vessels and fluid Last minutes to hours Resolve without discoloration/scarring Molecular and Cellular Immunology, 7 th ed.
14 Anaphylaxis, Angioedema, Urticaria Causes Approximately 1% of the population is dispensed outpatient epinephrine WAO Journal 2011; 4:13 37
15 Mast Cells and the Immune System
16 Immune System
17 Mast Cell Function Effector of the humoral immune system Fights off worm and bacterial infections
18 Mast Cell Dysfunction Anaphylaxis Systemic mastocytosis Mast cell activation syndrome (MCAS) MCAS and postural tachycardia syndrome (POTS)
19 Anaphylaxis Mechanism Molecular and Cellular Immunology, 7 th ed.
20 Anaphylaxis Histamine, leukotrienes, prostaglandins Pathophysiologic activity Smooth muscle spasm, mucus secretion, vasodilatation, increased vascular permeability Clinical correlates Wheeze, urticaria, angioedema, flush, itch, diarrhea and abdominal pain, hypotension, and rhinorrhea * * * * * Molecular and Cellular Immunology, 7 th ed.
21 Anaphylaxis Neutral proteases: tryptase Pathophysiologic activity Further activation of mast cells Clinical correlates Can magnify response due to further mast cell activation Tissue damage * Molecular and Cellular Immunology, 7 th ed.
22 Systemic Mastocytosis Excess growth of mast cells and accumulation in 1 or more organs 93% of cases due to a mutation of c-kit gene (KIT D816V) Symptoms are due to mast cell mediator release Rare: 1 in 20,000-40,000 More common in Caucasians
23 Systemic Mastocytosis Symptoms CNS: 10-90% Const: 12-56% GI abdominal pain, diarrhea, nausea/vomiting Skin itching/flushing, fixed skin lesions Cardiovascular (CV) fast heart rate, loss of consciousness, anaphylaxis Nervous system (CNS) headache, confusion Musculoskeletal (MS) bone pain Constitutional weakness, fatigue, malaise Respiratory shortness of breath, nasal symptoms Resp: 4-57% GI: 5-80% MS: 9-75% CV: 5-30% Skin: 8-95% Annals of allergy, asthma & immunology Jan;104(1):1-10.
24 Systemic Mastocytosis Presence of at least 1 major and 1 minor or 3 minor criteria in bone marrow or other organ Major Excessive mast cells on bone marrow biopsy*** Minor Excessive atypical mast cells c-kit D816V mutation Mast cells with surface markers (CD2, CD25, CD117) Serum tryptase >20 ng/ml
25 Systemic Mastocytosis Neuroendocrine evaluation Rule out pheochomocytoma, VIPoma, carcinoid syndrome Multispecialty approach likely necessary
26 Systemic Mastocytosis Avoid triggers Alcohol Spicy foods NSAIDs Narcotics Intense exercise Stinging insects Stress Block mast cell related symptoms H1 Antihistamines H2 Antihistamines Epinephrine Cromolyn LTRA Steroids Chemotherapy only if severe
27 MCAS Newly recognized disorder No excessive growth of mast cells Symptoms are due to mast cell mediator release Demographics Females: 89% of cases in one series Can happen in any age group On average, 4.6 years before referral
28 MCAS Symptoms CNS: 83% Abdominal pain (94%) Dermatographism (89%) Flushing (89%) Headache (83%) Poor concentration and memory (67%) Diarrhea (67%) Nose and eye symptoms (39%) Asthma (39%) Anaphylaxis (17%) Resp: 39% GI: 94% CV: 17% Skin: 89% The Journal of allergy and clinical immunology Jul;128(1): e2.
29 MCAS Clinical history Laboratory evaluation Serum total tryptase, 24-hour urine for histamine, N-methylhistamine, prostaglandin D2 Rule out other causes, including systemic mastocytosis (bone marrow biopsy) Neuroendocrine evaluation
30 MCAS Avoid triggers Alcohol Spicy foods NSAIDs Narcotics Intense exercise Stinging insects Stress Block mast cell related symptoms H1 Antihistamines H2 Antihistamines Epinephrine Cromolyn LTRA Steroids
31 MCAS and POTS Postural tachycardia syndrome (POTS) Rare, disabling condition High heart rate with standing More common in young females Unclear cause Poor nerve signaling (neuropathic) Excessive adrenal activation (hyperadrenergic) Some patients with flushing, suggesting mast cells might be involved
32 MCAS and POTS Symptoms CNS: 63% Const: 88% GI nausea/vomiting, diarrhea Skin flushing Cardiovascular (CV) fast heart rate, lightheadedness, loss of consciousness Nervous system (CNS) headache, confusion Constitutional weakness, fatigue, dizziness, malaise, anxiety Respiratory shortness of breath, nasal symptoms Resp: 38% GI: 38% CV: 100% Skin: 100% Hypertension Mar;45(3):
33 MCAS and POTS Tilt table testing Evaluation and treatment as with MCAS Trigger avoidance Exercise Prolonged standing After meals Premenstrual Heat intolerance Emotional stress
34 Case Presentation Mast Cell Evaluation Tryptase with episode 26.7 (elevated) Urine histamine with episode elevated Baseline tryptase NL Bone marrow NL Neuroendocrine Evaluation Urine/serum metanephrines NL Urine/serum catecholamines NL GI scope for carcinoid NL Urine 5 -HIAA NL VIP NL Cortisol NL Neurokinin A NL CT scan of chest and abdomen NL
35 Case Presentation Best diagnosis: MCAS The patient was transitioned to more appropriate treatment
36 Epinephrine Autoinjector
37 Treatment H1-Antihistamines Decrease itch, flush, urticaria, sneezing, and rhinorrhea Do not prevent or relieve obstruction to airflow or hypotension/shock Cetirizine, doxepin, cyproheptadine H2-Antihistamines Ranitidine Ann Emerg Med 2000;36:462-8.
38 Treatment Glucocorticoids Pharmacologic effects Switch off transcription of activated genes that encode pro-inflammatory proteins Clinical relevance Onset of action takes several hours Used to prevent and relieve mast cell related symptoms Ann Allergy Asthma Immunol 2005;95:
39 Treatment Leukotriene modifying agents (LTMA) Montelukast, zafirlukast, zileuton Cromones (mast cell stabilizer) Cromolyn GI symptoms only Dosing very important
40 Case Presentation Changed to: Cetirizine 20mg twice a day (H1) Ranitidine 300mg twice a day (H2) Start slow prednisone wean Reviewed epinephrine autoinjector use and indications
41 Case Presentation He has had only one mild episode including facial flushing, nausea and stomach pain No Emergency Department visit Added zafirlukast 20mg twice a day (LTMA) No episodes since then
42 Resources Bains SN, Hsieh FH. Current approaches to the diagnosis and treatment of systemic mastocytosis. Annals of allergy, asthma & immunology Jan;104(1):1-10. Hamilton MJ, Hornick JL, Akin C, et al. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. The Journal of allergy and clinical immunology Jul;128(1): e2. Shibao C, Arzubiaga C, Roberts LJ, 2nd, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension Mar;45(3): Pardanani A. Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. American journal of hematology Apr;87(4):
43 Resources American Academy of Allergy, Asthma, and Immunology The Mastocytosis Society The Elephant Project Dr. Peter Vadas and Sarah Leach
44 Conclusions Mast cell disorders are relatively rare but severe Patient history is extremely important Extensive evaluation and a multispecialty approach may be necessary to rule out all probable causes Good outcomes with appropriate treatment
45 Questions
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