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Mast Cell Disorders
Keith Berndtson, MD
Diagnosis and Treatment
Warning
Signs and symptoms of mast cell disorders can be extreme and
seemingly illogical. They are triggered by medications, supplements,
foods, environmental chemicals, emotional reactions, and more.
While many triggers are documented, mast cell activation patterns
are highly personal and unique to each individual.
Patients will have multiple sensitivities and many will not qualify as
true allergies. The suffering caused by these conditions is
compounded by delays in diagnosis. Patients are often labeled with
an anxiety disorder.
The increasing incidence of mast cell disorders correlates with
increasing exposure to noxious molecules in our environment.
There is a pressing need for increased physician awareness of these
disorders and current methods of diagnosis and treatment.
The mysterious,
fully equipped,
ready for anything
mast cell
What are Mast Cells?
Mast cells are marrow-derived immune cells that home to
varied tissue compartments where they carry out roles in host
defenses against infectious pathogens, allergens, toxins, and
autoimmune disease.
They are essential to the innate immune response and they
participate in both positive and negative regulation of the
adaptive immune response.
Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome.
Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18.
Beaven M. Our perception of the mast cell from Paul Ehrlich to now. European Journal of Immunology. 2009 Jan;39(1):11-25.
What are Mast Cells?
Mast cells contain Toll-like receptors (TLRs) and receptors for
estrogen, progesterone, CRH, and alpha-MSH. They also
contain receptors for cytokines and chemokines, nerve growth
factor, C3a, C5a, IgE, IgG, and other immune system mediators.
Derived from bone marrow, mast cells circulate in the blood as
progenitor cells and acquire their specific roles in processes
regulated by local tissue mediators.
Beaven M. Our perception of the mast cell from Paul Ehrlich to now. European Journal of Immunology. 2009 Jan;39(1):11-25.
Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome.
Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18.
Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function.
Mucosal Immunology. 2010;3:111-128.
Mast Cell Heterogeneity
Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function.
Mucosal Immunology. 2010;3:111-128.
Mast Cell Functions
Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function.
Mucosal Immunology. 2010;3:111-128.
Mast Cells vs. Pathogens
Mast Cells vs. Viruses
Upper respiratory viral infections worsen allergic asthma,
suggesting increased activation of mast cells during infection.
Mast cells recognize the presence of double-stranded viral
RNA and respond by releasing: IL-29, interferon-alpha,
interferon-beta, and tumor necrosis factor alpha.
Virally infected mast cells respond by releasing the anti-viral
proteins: MxA and IFIT3.
Stimulation of mast cell TLR3 induces mast cell recruitment of
anti-viral T cells.
Lappalainen J, et al. Intracellular RNA recognition pathway activates strong anti-viral response in human mast cells. Clinical and
Expermental Immunology. 2013 Apr;172(1):121-8.
Orinska Z, et al. TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment. Blood. 2005;106:978-987.
Mast Cells vs. Parasites
Mast cells offer a first line of defense against parasitic
pathogens. They are preferentially located in organs targeted
by parasites, where they release proteases, recruit neutrophils,
and regulate vessel permeability.
Mast cells release antimicrobial peptides. Their early innate
immune system signal transmissions play a critical role in
priming adaptive immune responses.
Metz M, Maurer M. Mast cells: key effectors in immune response. Trends in Immunology. 2007;28:234-241.
Mast Cells vs. Yeast
and Fungal Forms
Parasite antigen stimulation of TLRs) and C-type lectin
receptors (CLRs) initiates a wide range of mast cell IgE
receptors resulting in the release of pro-inflammatory
cytokines, chemokines, and other pre-stored mediators of
inflammation.
The release of pre-formed mediators of inflammation is
followed by the production of specific IgG1 antibodies against
parasite antigens.
Saluja R, Metz M, Maurer M. Role and relevance of mast cells in fungal infections. Frontiers in Immunology. 2012 Jun;13(3):146.
Mast Cells vs. Bacteria
Mast cells express most TLRs on their membrane surfaces.
TLR binding triggers distinctive patterns of mast cell
activation including the release of antimicrobial peptides
and the production of complement-mediated membrane
attack complexes.
Mast cell activation also results in the production of non-
preformed mediators of inflammation including matrix
metallproteinase-9 (MMP-9).
Ikeda T, Funaba M. Altered function of murine mast cells in response to lipopolysaccharide and peptidoglycan. Immunology
Letters. 2003;88:21-26.
McCurdy J. et al. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production
from human mast cells. Journal of Immunology. 2003;170:1625-1629.
Mast Cells vs. Allergens
Allergen detection leads to mast cell histamine release, tight
junction disruption, increased permeability, and recruitment
of lymphocytes and eosinophils.
In skin, this leads to wheal and flare reactions. In the gut,
this leads to intestinal hyper-permeability, smooth muscle
contraction, altered water and ion transport, and intestinal
symptoms. In the lungs, this leads to smooth muscle
contraction, mucus production, and airway remodeling.
Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function.
Mucosal Immunology. 2010;3:111-128.
Mast Cells vs. Toxins
Mast cells are known to initiate an immediate IgE-dependent
hypersensitivity response to venoms.
Mast cells can also be activated by various endotoxins and
exotoxins.
It is not known whether mold or bacterial toxins activate mast
cell responses, but mast cells release VEGF and MMP-9,
markers affected in biotoxin-mediated inflammation.
Beghdadi W, Blank U, et al, et al. Mast cells as cellular sensors in inflammation and immunity. Frontiers in Immunology. 2011;2:37-91.
Mast Cells vs. Wounds
Mast cells also play non-immunological roles that include
angiogenesis, tissue remodeling, and wound healing.
Gilfillan AM, Beaven MA. Regulation of mast cell response in health and disease. Critical Reviews of Immunology. 2011;31(6):475-529.
Noli C, Miolo A. The mast cell in wound healing in tumor growth. Critical Reviews of Immunology. 2011;31(6):475-529.
What are Mast Cells?
Master Coordinators of
Host Defenses Against
Noxious Incitants
The Good
• An essential player in the body’s innate immune response.
• They patrol the front lines: skin, connective tissues and mucus
membranes.
• They release chemical alarms to summon defenses against
pathogens, allergens, toxins, and other noxious incitants.
• These chemicals include histamine, serotonin, heparin, tryptase,
chymase, chemokines, eicosanoids, cytokines (TNF-alpha, IL-6,
IL-1beta), leukotrienes, antimicrobial peptides, growth factors,
substance P, and endothelin.
Mast Cells: The Good,
the Bad, and the Ugly
Beaven M. Our perception of the mast cell from Paul Ehrlich to now. European Journal of Immunology. 2009 Jan;39(1):11-25.
Mast Cell Mediator Pathways
Innate immune
response
Adaptive
immune
response
Inflammation
Mast Cells: The Good,
the Bad, and the Ugly
The Bad
Over-activation of mast cells can lead to:
• Allergic disease/Asthma/Anaphylaxis
• Eczema/atopic dermatitis
• Migraines/neurological disorders
• Autoimmune disorders
• Gastrointestinal disorders
• Unexplained multi-symptom illnesses
Histamine is only one of many inflammatory elements released by
mast cells. Excess release of mast cell-derived chemicals results in
mast cell-related inflammation.
Theoharides T, et al. Mast cells and inflammation. Biochimica et Biophysica Acta. 2012 Jan;1822(1):21-33.
Mast Cells: The Good,
the Bad, and the Ugly
The Bad
• Abnormal mast cell proliferation results in
mastocytosis, which can lead to mast cell tumors
and severe forms of cutaneous or systemic disease.
• Systemic mastocytosis commonly results in an
unexplained multi-system, multi-symptom illness
with damage to multiple organ systems that can go
unrecognized in multiple medical settings.
Mast Cells: The Good,
the Bad, and the Ugly
The Ugly
Mast Cells Disorders
• Idiopathic (non-clonal) mast cell activation syndrome (also
known as nc-MCAS): occurs more often in women for whom
MC triggers are usually unknown. Idiopathic anaphylaxis and
mastocytosis should be ruled out. Often indistinguishable
from secondary MCAS.
• Secondary mast cell activation syndrome (another form of
nc-MCAS): related to underlying inflammation caused by
allergy, infection, toxicity, cancer, or autoimmune activity.
Picard M, et al. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndrome.
Clinical Therapeutics. 2013 May;35(5):548-62.
The Most Common Forms of
Mast Cell Activation Syndrome
Mast Cells Disorders
• Monoclonal mast cell activation syndrome (MMAS): systemic
reactions to hymenoptera stings or unexplained anaphylaxis
with high baseline tryptase. Bone marrow biopsy shows
monoclonal MCs but not mastocytosis. Thought to be rare.
• Mastocytosis (SM): presenting as cutaneous or systemic
variants.
Picard M, et al. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndrome.
Clinical Therapeutics. 2013 May;35(5):548-62.
The Less Common Forms of
Mast Cell Activation Syndrome
Mast Cells Disorders
• Histaminosis: commonly induced by exposure to
histamine from foods; rarely, an acute syndrome caused by
scromboid poisoning (due to tainted seafood high in
histamine).
• Histamine intolerance: sensitivity to histamine from foods
and/or from reduced histamine breakdown. Can involve
other mast cell mediators as well.
Bodmer S, et al. Biogenic amines in foods: histamine and food processing. Inflammation Research. 1999 Jun;48(6):296-300.
Histamine-Overdrive Mast Cell Disorders
Maintz L, Novak N. Histamine and histamine intolerance. American Journal of Clinical Nutrition. 2007 May;85(5):1185-96.
Maintz L, et al. Evidence for reduced histamine degradation capacity in a subgroup of patients with atopic eczema.
Journal of Allergy and Clinical Immunology. 2006 May;117(5):1106-12.
Histamine Breakdown
DAO HMT
DAO
Diamine Oxidase:
operates outside cells
in the bloodstream
and peripheral tissues
Cu and P-5-P dependent
oxidative deamination
HMT
Histamine methyltransferase:
operates inside cells and in
the central nervous system
SAMe dependent
N-methylation
Histamine Synthesis
Inert end product Inert end product
Histamine
Histidine
HDC
HDC
Histidine decarboxylase:
operates in all cells
P-5-P dependent
Histamine Receptors
H1: itching, vasodilation, leaky vessels
bronchoconstriction
H2: gastric acid, heart rate, immune stimulation
smooth muscle relaxation
H3: reduced CNS ACh, serotonin, norepinephrine
H4: mediates mast cell production, chemotaxis
Histamine Receptors
and Breakdown Pathways
Reduced central or peripheral breakdown
of histamine can lead to:
Histamine Intolerance
• Rashes
• Headaches
• Fatigue
• Hives or flushing
• Allergies
• Dysmenorrhea
• Estrogen dominance
• GI disturbances
• Dysrhythmias
• Arthritis
• Central, peripheral and/or autonomic neurologic disorders
Diagnosis
Histamine Intolerance
• At least two typical symptoms of histamine intolerance
• Diamine oxidase (DAO) activity:
<3 U/mL: likely
<10 U/mL: possible
>10 U/mL: improbable
Treatment
• Histamine-free diet for 4 weeks
• Daily symptom log
• Histamine capsule challenge with medical monitoring
Histamine Intolerance
Potential indirect causes of histamine intolerance
due to reduced histamine breakdown:
• Low pyridoxal-5-phosphate reserves (active form of vit. B6).
• Low copper reserves.
• Low S-adenosyl methionine reserves (SAMe).
• Low methylation capacity (weak MTHFR or secondarily related
genomic variants).
• Excess methylation demand (eg, chronic oxidative stress and
inflammation, and/or chronic emotional stress).
Histamine
Neurotransmitter
changes
Mast cell
proliferation
cGMP release
cAMP release
Gastric acid
release
Smooth muscle
constriction
Estrogen
metabolism
Increase mucus
secretion
Endothelial
hyperpermeability
Pain fiber
stimulation
Tachycardia,
Dysrhythmias
Vasodilation,
Orthostasis
H3 H4
H2
H2
H1
H1 H1
H1/2
H1
H1/2
H4
H1/2
CNS
Cardiovascular
Headaches
Nausea
Vertigo
Irritability
Anxiety
Depression
Hypotension
Appetite changes
Cognitive dysfunction
Thermal dysregulation
Reduced motor control
Hypertension
Dysrhythmia
Tachycardia
Orthostasis
Skin
Itching
Flushing
Heat
Hives
Pain
Palor
Tenderness
Swelling
Respiratory
Nasal congestion
Runny nose
Sneezing
Itchy, watery eyes
Bronchoconstriction
Mucus production
wheezing
Dyspnea
Menstrual
Pelvic pain
Dysmenorrhea
PMS
Endometriosis
Gastrointestinal
Nausea
Stomach aches
Bloating
Cramping
Constipation
Loose stools
Leaky gut
Food sensitivities
Gut flora imbalance
Crohn’s disease
Bone Marrow
Increased mast cell
production by bone
marrow can lead to
mastocytosis.
Histamine Pathophysiology
Mastocytosis
• Prevalence: 1 in 10,000 (under-diagnosis suspected)
• Prognosis: worse for patients with widespread skin
involvement, increased baseline tryptase levels, or extensive
blistering.
• Diagnosis: based on bone marrow biopsy.
• Conventional treatment options: antihistamines,
leukotriene antagonists (eg, montelukast), mast cell stabilizers
(eg, cromolyn sodium), proton pump inhibitors, albuterol,
corticosteroids
• Integrative treatment options: strategic nutrition-based
food choices and dietary supplementation, exercise, stress
reduction.
Mast cells and
Irritable Bowel Syndrome
1. Grover M, et al. Postinfectious irritable bowel syndrome: mechanisms related to pathogens. Neurogastroenterology and
Motility. 2014 Feb;26(2):156-67.
2. Matricon J, et al. Review article: associations between immune activation, intestinal hyperpermeability, and irritable
bowel syndrome. Alimentary Prhamacology and Therapeutics. 2012 Dec;36(11-12):1009-31.
3. Beghdadi W, Blank U, et al, et al. Mast cells as cellular sensors in inflammation and immunity. Frontiers in Immunology.
2011;2:37-91.
• Mast cell activation plays a role in post-infectious IBS. (1)
• Mast cell degranulation associates with cytokine
alterations and intestinal hyperpermeability in patients
with IBS. (2)
• Mast cell hyperplasia is seen in inflammatory bowel
disorders. (3)
Mast cells and Interstitial
Cystitis/Bladder Pain Syndrome
1. Sant GR, Theoharides T, et al. The mast cell in interstitial cystitis. Urology. 2007 Apr;69(4 Suppl):34-40.
2. Rudick CN, et al. Mast cell-derived histamine mediates cystitis pain. PLoS One. 2008 May 7;3(5):e2096.
3. Lu J, et al. MCP-1-induced histamine release from mast cells is associates with development of interstitial
cystitis/bladder pain syndrome in rat models. Mediators of Inflammatio. 2012:358184.
• Current evidence from clinical and laboratory studies
confirms that mast cells play a central role in the pathogenesis
and pathophysiology of interstitial cystitis. (1)
• Mast cells promote cystitis pain and bladder pathology
through separable actions of histamine and tumor necrosis
factor. (2)
•Antigen ingress into the bladder submucosal layer results in
mast cell degranulation. (3)
Mast Cells and
Coronary Artery Disease
Alivizos M, et al. Stress triggers coronary mast cells leading to cardiac events. Annals of Allergy, Asthma, and Immunology.
2014 Apr;112(4):309-316.
Stress triggers mast cell release
of inflammatory cytokines
• Mast cell activation plays a role in coronary inflammation, coronary
disease, coronary hypersensitivity, and acute coronary syndromes.
• People with mastocytosis or myalgic encephaplitis/chronic fatigue
syndrome are particularly prone to coronary hypersensitivity reactions.
• Stress precipitates and worsens activation of mast cells via activation of
surface receptors by corticotropin releasing hormone (CRH) and other
hypothalamic neuropeptide regulators.
• Mast cell stimulation by CRH and neurotensin triggers release of IL-6,
which is an independent risk factor for myocardial ischemia.
Mast Cells and the
Blood-Brain Barrier
image: learningneuroradiolgy.blogspt.com/2103/case-1430-choroid-plexus-xanthogranuloma
Acute stress triggers CRH production. CRH activates histamine
release by mast cells, which leads to increased blood-brain barrier
permeability. This implicates mast cells in neuroinflammatory
disorders including multiple sclerosis, neuroborreliosis, and
chronic inflammatory response syndrome related to poor biotoxin
clearance.
Couturier N, Liblau RS, et al. Mast cell transcripts are increased within and outside multiple sclerosis lesions. Journal of
Neuroimmunology. 2008 Mar;195(1-2):176-85.
Esposito P, Theoharides T, et al. Acute stress increases permeability of the blood-brain barrier through activation of mast
cells. Brain Research. 2001;888(1):117-127.
The Epigenetics of Mast Cell
Activation Syndrome
• Aberrant activation of mast cells is a heritable trait.
• Epigenetic mechanisms are involved in nc-MCAS.
• nc-MCAS associates with alterations in DNA methylation
related to genes responsible for DNA maintenance and repair.
• “Epigenetic processes could substantially contribute to the
transgenerational transmission of nc-MCAS.”
Haenisch B, et al. Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation
syndrome. Immunogenetics. 2014 May;66(5):287-97.
Diagnostic Algorithm for nc-MCAS
Patient with signs and symptoms of mast cell activation in at least 2 organ systems
Consider and rule out other medical disorders that may explain symptoms
(eg, carcinoid, pheochromocytoma, gastrinoma, VIPoma, porphyria)
Evaluate for mast cell clonality
(serum tryptase, bone marrow)
Classify as MMAS or SM
Treat and monitor
Yes
Evaluate for mast cell mediators when patient is symptomatic
(serum tryptase, N-methylhistamine, PGD2)
No
Trial of meds to block mast cell mediators,
Lifestyle to reduce mast cell activation
Trial of meds to block mast cell mediators,
Lifestyle to reduce mast cell activation
Positive Negative
Likely nc-MCAS, keep
treating, consider alternative
Not improved in 3 to 6
months, search for alternative
Equivocal responseGood response Good response
May have nc-MCAS, keep
treating, consider alternative
Has nc-MCAS, keep treating,
and monitor
Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome.
Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18. Flow diagram slightly modified to include lifestyle-based therapies.
When to Suspect MCAS
• Patient presents with a chronic (persistent or recurrent), waxing and waning
or slowly progressive multisystem polymorbidity that is generally, but not
necessarily, presents in a context of underlying chronic inflammation.
• Syndrome usually acquired early in life via interaction of environmental
factors with heritable risk factors.
• Virtually all of the syndrome’s manifestations are non-specific, leading to
decades of unexplained illness and incorrect diagnoses that poorly respond to
empiric therapies.
• Systemic MC disease of any form is not presently curable. The aim of therapy
is to control symptoms through trigger avoidance, diet , lifestyle, supplements,
and medications.
• Once MCAS suspected, a methodical, persistent trial-and-error approach
usually leads to helpful therapy.
Molderings GJ, Afrin LB, et al. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic
options. Journal of Hematology and Oncology. 2011;4:10-29.
History
When to Suspect MCAS
• Skin: flushing, urticaria, pruritis, dermatographism, urticaria pigmentosa,
angioedema, eczema.
• Gastrointestinal: abdominal pain, cramping, diarrhea, gas, bloating, reflux.
• Pulmonary: cough, wheezing, air hunger, shortness of breath.
• Upper Respiratory: nasal congestion, throat itching, soreness, or swelling.
• Cardiovascular: fatigue, rapid heart rate, low blood pressure, fainting, near-
fainting.
• Neurological: headaches, difficulty concentrating, anxiety, irritability,
fainting, near fainting.
Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome.
Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18. Flow diagram slightly modified to include lifestyle-based therapies.
Common Signs and Symptoms
Alvarez-Twose I, et al. Clinical, biological, and molecular characteristics of of clonal mast cell disorders presenting with
systemic mast cell activation symptoms. Journal of Allergy and Clinical Immunology. 2010 Jun;125(6):1269-1278.
Predictors of clonal MCAS
• Male gender
• Absence of urticaria or angioedema
• Absence of near-fainting or fainting
• Serum total tryptase level >25 ng/mL
Bone marrow biopsy should be considered in patients with a
serum total tryptase >20 ng/mL, or >11.4 ng/mL in patients
with a history of significant blood pressure drops or fainting.
Treatment for MCAS
Avoid Known Triggers
• Temperature extremes, sunlight
• Mechanical irritation
• Alcohol, illicit drugs
• High histamine foods, food additives
• Stress
• Certain anesthetic agents
• Environmental biotoxins or man-made chemicals
Treatment for MCAS
Medications
• H1-histamine receptor antagonists (diphenhydramine,
hydroxyzine, cetirizine, fexofenadine)
• H2-histamine receptor antagonists (ranitidine, famotidine)
• Mast cell stabilizers (NasalCrom, GastroCrom)
• Leukotriene inhibitor (Singulair, montelukast)
Treatment for MCAS
Supplements that Often Help
• Neuroprotek (quercetin, rutin, luteolin) Algonot
• Histamine Block (diamine oxidase)* Seeking Health
• ProBiota (may reduce histamine in some people) Seeking Health
• Natural D-Hist (vit C, quercetin, nettles, bromelain, NAC) Orthomolecular
• Quercetin + C (from Saphora japonica and sago palm) TwinLabs
• Mangosteen (lowers histamine and prostaglandins) Source Naturals
* Use with caution if allergic to pork
Diet and Nutrition in the
Treatment of Mast Cell Disorders
Helpful Nutrients Helpful Foods* Harmful foods
antioxidants fresh fruits oxidized foods (fried, smoked)
bioflavonoids fresh vegetables processed foods
natural antihistamines legumes (beans) foods with additives
omega 3 fatty acids fresh meats and fish fermented foods
mangosteen most leafy herbs high histamine foods**
*Some persons may not tolerate helpful foods due to other types of reactivity.
**Highly aggressive restriction of histamine-containing foods may be
counterproductive. The body needs histamine and may induce a compensatory
increase in histamine synthesis when histamine support from food is very low.
Diet and Nutrition in the
Treatment of Mast Cell Disorders
Some high histamine foods
pickles seeds beer
mayonnaise nuts wine
sauerkraut chocolate champagne
vinegar cocoa shellfish
dried fruits processed meats tofu cheese
yeast canned vegetables mushrooms
food additives egg whites aged cheeses
tomatoes spices spinach
Keep meats and fish refrigerated! Eating meat or fish left out too long can cause histamine poisoning!
Diet and Nutrition in the
Treatment of Mast Cell Disorders
Some foods with anti-histamine effects
• Apples: rich in quercitin
• Carrots: rich in vitamin A
• Watercress: inhibits histamine release
• Broccoli: H2 receptor antagonist
• Ginger: H2 receptor antagonist
• Thyme: anaphylaxis inhibitor
• Fennel: antioxidants, antihistamine, anti-inflammatory
• Turmeric: stabilizes mast cells, inhibits histamine release
Visit www.lowhistaminechef.com to access some of the best information available on
moderating mast cell activation through lifestyle change.
Diet and Nutrition in the
Treatment of Mast Cell Disorders
You can’t avoid histamine containing foods while on an otherwise toxic
diet and expect to be well. The body works in conjunction with
thousands of plant-based nutrients. If a low-histamine diet works it is in
large part due to the multiple anti-inflammatory effects of whole foods.
- Dr. Joel Fuhrman (food micronutrient expert)
On low-histamine diets
I don’t believe that any food list can address the mystery and beauty of
nature, the body’s relationship to this mystery, or the power of our
minds to make us sick or well. Histamine-lowering foods work only
when accompanied by an anti-inflammatory diet rich in whole foods,
and a healthy, stress-reducing mind-body lifestyle.
- Yasmina Ykelenstam (The Low Histamine Chef)
Patient-centered
systems medicine.
15 N. Prospect
Park Ridge, IL 60068
847-232-9800
www.parkridgemultimed.com

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Mast cell disorders

  • 1. Mast Cell Disorders Keith Berndtson, MD Diagnosis and Treatment
  • 2. Warning Signs and symptoms of mast cell disorders can be extreme and seemingly illogical. They are triggered by medications, supplements, foods, environmental chemicals, emotional reactions, and more. While many triggers are documented, mast cell activation patterns are highly personal and unique to each individual. Patients will have multiple sensitivities and many will not qualify as true allergies. The suffering caused by these conditions is compounded by delays in diagnosis. Patients are often labeled with an anxiety disorder. The increasing incidence of mast cell disorders correlates with increasing exposure to noxious molecules in our environment. There is a pressing need for increased physician awareness of these disorders and current methods of diagnosis and treatment.
  • 3. The mysterious, fully equipped, ready for anything mast cell
  • 4. What are Mast Cells? Mast cells are marrow-derived immune cells that home to varied tissue compartments where they carry out roles in host defenses against infectious pathogens, allergens, toxins, and autoimmune disease. They are essential to the innate immune response and they participate in both positive and negative regulation of the adaptive immune response. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18. Beaven M. Our perception of the mast cell from Paul Ehrlich to now. European Journal of Immunology. 2009 Jan;39(1):11-25.
  • 5. What are Mast Cells? Mast cells contain Toll-like receptors (TLRs) and receptors for estrogen, progesterone, CRH, and alpha-MSH. They also contain receptors for cytokines and chemokines, nerve growth factor, C3a, C5a, IgE, IgG, and other immune system mediators. Derived from bone marrow, mast cells circulate in the blood as progenitor cells and acquire their specific roles in processes regulated by local tissue mediators. Beaven M. Our perception of the mast cell from Paul Ehrlich to now. European Journal of Immunology. 2009 Jan;39(1):11-25. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18.
  • 6. Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunology. 2010;3:111-128. Mast Cell Heterogeneity
  • 7. Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunology. 2010;3:111-128. Mast Cell Functions
  • 8. Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunology. 2010;3:111-128. Mast Cells vs. Pathogens
  • 9. Mast Cells vs. Viruses Upper respiratory viral infections worsen allergic asthma, suggesting increased activation of mast cells during infection. Mast cells recognize the presence of double-stranded viral RNA and respond by releasing: IL-29, interferon-alpha, interferon-beta, and tumor necrosis factor alpha. Virally infected mast cells respond by releasing the anti-viral proteins: MxA and IFIT3. Stimulation of mast cell TLR3 induces mast cell recruitment of anti-viral T cells. Lappalainen J, et al. Intracellular RNA recognition pathway activates strong anti-viral response in human mast cells. Clinical and Expermental Immunology. 2013 Apr;172(1):121-8. Orinska Z, et al. TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment. Blood. 2005;106:978-987.
  • 10. Mast Cells vs. Parasites Mast cells offer a first line of defense against parasitic pathogens. They are preferentially located in organs targeted by parasites, where they release proteases, recruit neutrophils, and regulate vessel permeability. Mast cells release antimicrobial peptides. Their early innate immune system signal transmissions play a critical role in priming adaptive immune responses. Metz M, Maurer M. Mast cells: key effectors in immune response. Trends in Immunology. 2007;28:234-241.
  • 11. Mast Cells vs. Yeast and Fungal Forms Parasite antigen stimulation of TLRs) and C-type lectin receptors (CLRs) initiates a wide range of mast cell IgE receptors resulting in the release of pro-inflammatory cytokines, chemokines, and other pre-stored mediators of inflammation. The release of pre-formed mediators of inflammation is followed by the production of specific IgG1 antibodies against parasite antigens. Saluja R, Metz M, Maurer M. Role and relevance of mast cells in fungal infections. Frontiers in Immunology. 2012 Jun;13(3):146.
  • 12. Mast Cells vs. Bacteria Mast cells express most TLRs on their membrane surfaces. TLR binding triggers distinctive patterns of mast cell activation including the release of antimicrobial peptides and the production of complement-mediated membrane attack complexes. Mast cell activation also results in the production of non- preformed mediators of inflammation including matrix metallproteinase-9 (MMP-9). Ikeda T, Funaba M. Altered function of murine mast cells in response to lipopolysaccharide and peptidoglycan. Immunology Letters. 2003;88:21-26. McCurdy J. et al. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. Journal of Immunology. 2003;170:1625-1629.
  • 13. Mast Cells vs. Allergens Allergen detection leads to mast cell histamine release, tight junction disruption, increased permeability, and recruitment of lymphocytes and eosinophils. In skin, this leads to wheal and flare reactions. In the gut, this leads to intestinal hyper-permeability, smooth muscle contraction, altered water and ion transport, and intestinal symptoms. In the lungs, this leads to smooth muscle contraction, mucus production, and airway remodeling. Moon TC, et al. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunology. 2010;3:111-128.
  • 14. Mast Cells vs. Toxins Mast cells are known to initiate an immediate IgE-dependent hypersensitivity response to venoms. Mast cells can also be activated by various endotoxins and exotoxins. It is not known whether mold or bacterial toxins activate mast cell responses, but mast cells release VEGF and MMP-9, markers affected in biotoxin-mediated inflammation. Beghdadi W, Blank U, et al, et al. Mast cells as cellular sensors in inflammation and immunity. Frontiers in Immunology. 2011;2:37-91.
  • 15. Mast Cells vs. Wounds Mast cells also play non-immunological roles that include angiogenesis, tissue remodeling, and wound healing. Gilfillan AM, Beaven MA. Regulation of mast cell response in health and disease. Critical Reviews of Immunology. 2011;31(6):475-529. Noli C, Miolo A. The mast cell in wound healing in tumor growth. Critical Reviews of Immunology. 2011;31(6):475-529.
  • 16. What are Mast Cells? Master Coordinators of Host Defenses Against Noxious Incitants
  • 17. The Good • An essential player in the body’s innate immune response. • They patrol the front lines: skin, connective tissues and mucus membranes. • They release chemical alarms to summon defenses against pathogens, allergens, toxins, and other noxious incitants. • These chemicals include histamine, serotonin, heparin, tryptase, chymase, chemokines, eicosanoids, cytokines (TNF-alpha, IL-6, IL-1beta), leukotrienes, antimicrobial peptides, growth factors, substance P, and endothelin. Mast Cells: The Good, the Bad, and the Ugly
  • 18. Beaven M. Our perception of the mast cell from Paul Ehrlich to now. European Journal of Immunology. 2009 Jan;39(1):11-25. Mast Cell Mediator Pathways Innate immune response Adaptive immune response Inflammation
  • 19. Mast Cells: The Good, the Bad, and the Ugly The Bad Over-activation of mast cells can lead to: • Allergic disease/Asthma/Anaphylaxis • Eczema/atopic dermatitis • Migraines/neurological disorders • Autoimmune disorders • Gastrointestinal disorders • Unexplained multi-symptom illnesses Histamine is only one of many inflammatory elements released by mast cells. Excess release of mast cell-derived chemicals results in mast cell-related inflammation.
  • 20. Theoharides T, et al. Mast cells and inflammation. Biochimica et Biophysica Acta. 2012 Jan;1822(1):21-33. Mast Cells: The Good, the Bad, and the Ugly The Bad
  • 21. • Abnormal mast cell proliferation results in mastocytosis, which can lead to mast cell tumors and severe forms of cutaneous or systemic disease. • Systemic mastocytosis commonly results in an unexplained multi-system, multi-symptom illness with damage to multiple organ systems that can go unrecognized in multiple medical settings. Mast Cells: The Good, the Bad, and the Ugly The Ugly
  • 22. Mast Cells Disorders • Idiopathic (non-clonal) mast cell activation syndrome (also known as nc-MCAS): occurs more often in women for whom MC triggers are usually unknown. Idiopathic anaphylaxis and mastocytosis should be ruled out. Often indistinguishable from secondary MCAS. • Secondary mast cell activation syndrome (another form of nc-MCAS): related to underlying inflammation caused by allergy, infection, toxicity, cancer, or autoimmune activity. Picard M, et al. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndrome. Clinical Therapeutics. 2013 May;35(5):548-62. The Most Common Forms of Mast Cell Activation Syndrome
  • 23. Mast Cells Disorders • Monoclonal mast cell activation syndrome (MMAS): systemic reactions to hymenoptera stings or unexplained anaphylaxis with high baseline tryptase. Bone marrow biopsy shows monoclonal MCs but not mastocytosis. Thought to be rare. • Mastocytosis (SM): presenting as cutaneous or systemic variants. Picard M, et al. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndrome. Clinical Therapeutics. 2013 May;35(5):548-62. The Less Common Forms of Mast Cell Activation Syndrome
  • 24. Mast Cells Disorders • Histaminosis: commonly induced by exposure to histamine from foods; rarely, an acute syndrome caused by scromboid poisoning (due to tainted seafood high in histamine). • Histamine intolerance: sensitivity to histamine from foods and/or from reduced histamine breakdown. Can involve other mast cell mediators as well. Bodmer S, et al. Biogenic amines in foods: histamine and food processing. Inflammation Research. 1999 Jun;48(6):296-300. Histamine-Overdrive Mast Cell Disorders Maintz L, Novak N. Histamine and histamine intolerance. American Journal of Clinical Nutrition. 2007 May;85(5):1185-96. Maintz L, et al. Evidence for reduced histamine degradation capacity in a subgroup of patients with atopic eczema. Journal of Allergy and Clinical Immunology. 2006 May;117(5):1106-12.
  • 25. Histamine Breakdown DAO HMT DAO Diamine Oxidase: operates outside cells in the bloodstream and peripheral tissues Cu and P-5-P dependent oxidative deamination HMT Histamine methyltransferase: operates inside cells and in the central nervous system SAMe dependent N-methylation Histamine Synthesis Inert end product Inert end product Histamine Histidine HDC HDC Histidine decarboxylase: operates in all cells P-5-P dependent Histamine Receptors H1: itching, vasodilation, leaky vessels bronchoconstriction H2: gastric acid, heart rate, immune stimulation smooth muscle relaxation H3: reduced CNS ACh, serotonin, norepinephrine H4: mediates mast cell production, chemotaxis Histamine Receptors and Breakdown Pathways
  • 26. Reduced central or peripheral breakdown of histamine can lead to: Histamine Intolerance • Rashes • Headaches • Fatigue • Hives or flushing • Allergies • Dysmenorrhea • Estrogen dominance • GI disturbances • Dysrhythmias • Arthritis • Central, peripheral and/or autonomic neurologic disorders
  • 27. Diagnosis Histamine Intolerance • At least two typical symptoms of histamine intolerance • Diamine oxidase (DAO) activity: <3 U/mL: likely <10 U/mL: possible >10 U/mL: improbable Treatment • Histamine-free diet for 4 weeks • Daily symptom log • Histamine capsule challenge with medical monitoring
  • 28. Histamine Intolerance Potential indirect causes of histamine intolerance due to reduced histamine breakdown: • Low pyridoxal-5-phosphate reserves (active form of vit. B6). • Low copper reserves. • Low S-adenosyl methionine reserves (SAMe). • Low methylation capacity (weak MTHFR or secondarily related genomic variants). • Excess methylation demand (eg, chronic oxidative stress and inflammation, and/or chronic emotional stress).
  • 29. Histamine Neurotransmitter changes Mast cell proliferation cGMP release cAMP release Gastric acid release Smooth muscle constriction Estrogen metabolism Increase mucus secretion Endothelial hyperpermeability Pain fiber stimulation Tachycardia, Dysrhythmias Vasodilation, Orthostasis H3 H4 H2 H2 H1 H1 H1 H1/2 H1 H1/2 H4 H1/2 CNS Cardiovascular Headaches Nausea Vertigo Irritability Anxiety Depression Hypotension Appetite changes Cognitive dysfunction Thermal dysregulation Reduced motor control Hypertension Dysrhythmia Tachycardia Orthostasis Skin Itching Flushing Heat Hives Pain Palor Tenderness Swelling Respiratory Nasal congestion Runny nose Sneezing Itchy, watery eyes Bronchoconstriction Mucus production wheezing Dyspnea Menstrual Pelvic pain Dysmenorrhea PMS Endometriosis Gastrointestinal Nausea Stomach aches Bloating Cramping Constipation Loose stools Leaky gut Food sensitivities Gut flora imbalance Crohn’s disease Bone Marrow Increased mast cell production by bone marrow can lead to mastocytosis. Histamine Pathophysiology
  • 30. Mastocytosis • Prevalence: 1 in 10,000 (under-diagnosis suspected) • Prognosis: worse for patients with widespread skin involvement, increased baseline tryptase levels, or extensive blistering. • Diagnosis: based on bone marrow biopsy. • Conventional treatment options: antihistamines, leukotriene antagonists (eg, montelukast), mast cell stabilizers (eg, cromolyn sodium), proton pump inhibitors, albuterol, corticosteroids • Integrative treatment options: strategic nutrition-based food choices and dietary supplementation, exercise, stress reduction.
  • 31. Mast cells and Irritable Bowel Syndrome 1. Grover M, et al. Postinfectious irritable bowel syndrome: mechanisms related to pathogens. Neurogastroenterology and Motility. 2014 Feb;26(2):156-67. 2. Matricon J, et al. Review article: associations between immune activation, intestinal hyperpermeability, and irritable bowel syndrome. Alimentary Prhamacology and Therapeutics. 2012 Dec;36(11-12):1009-31. 3. Beghdadi W, Blank U, et al, et al. Mast cells as cellular sensors in inflammation and immunity. Frontiers in Immunology. 2011;2:37-91. • Mast cell activation plays a role in post-infectious IBS. (1) • Mast cell degranulation associates with cytokine alterations and intestinal hyperpermeability in patients with IBS. (2) • Mast cell hyperplasia is seen in inflammatory bowel disorders. (3)
  • 32. Mast cells and Interstitial Cystitis/Bladder Pain Syndrome 1. Sant GR, Theoharides T, et al. The mast cell in interstitial cystitis. Urology. 2007 Apr;69(4 Suppl):34-40. 2. Rudick CN, et al. Mast cell-derived histamine mediates cystitis pain. PLoS One. 2008 May 7;3(5):e2096. 3. Lu J, et al. MCP-1-induced histamine release from mast cells is associates with development of interstitial cystitis/bladder pain syndrome in rat models. Mediators of Inflammatio. 2012:358184. • Current evidence from clinical and laboratory studies confirms that mast cells play a central role in the pathogenesis and pathophysiology of interstitial cystitis. (1) • Mast cells promote cystitis pain and bladder pathology through separable actions of histamine and tumor necrosis factor. (2) •Antigen ingress into the bladder submucosal layer results in mast cell degranulation. (3)
  • 33. Mast Cells and Coronary Artery Disease Alivizos M, et al. Stress triggers coronary mast cells leading to cardiac events. Annals of Allergy, Asthma, and Immunology. 2014 Apr;112(4):309-316. Stress triggers mast cell release of inflammatory cytokines • Mast cell activation plays a role in coronary inflammation, coronary disease, coronary hypersensitivity, and acute coronary syndromes. • People with mastocytosis or myalgic encephaplitis/chronic fatigue syndrome are particularly prone to coronary hypersensitivity reactions. • Stress precipitates and worsens activation of mast cells via activation of surface receptors by corticotropin releasing hormone (CRH) and other hypothalamic neuropeptide regulators. • Mast cell stimulation by CRH and neurotensin triggers release of IL-6, which is an independent risk factor for myocardial ischemia.
  • 34. Mast Cells and the Blood-Brain Barrier image: learningneuroradiolgy.blogspt.com/2103/case-1430-choroid-plexus-xanthogranuloma Acute stress triggers CRH production. CRH activates histamine release by mast cells, which leads to increased blood-brain barrier permeability. This implicates mast cells in neuroinflammatory disorders including multiple sclerosis, neuroborreliosis, and chronic inflammatory response syndrome related to poor biotoxin clearance. Couturier N, Liblau RS, et al. Mast cell transcripts are increased within and outside multiple sclerosis lesions. Journal of Neuroimmunology. 2008 Mar;195(1-2):176-85. Esposito P, Theoharides T, et al. Acute stress increases permeability of the blood-brain barrier through activation of mast cells. Brain Research. 2001;888(1):117-127.
  • 35. The Epigenetics of Mast Cell Activation Syndrome • Aberrant activation of mast cells is a heritable trait. • Epigenetic mechanisms are involved in nc-MCAS. • nc-MCAS associates with alterations in DNA methylation related to genes responsible for DNA maintenance and repair. • “Epigenetic processes could substantially contribute to the transgenerational transmission of nc-MCAS.” Haenisch B, et al. Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation syndrome. Immunogenetics. 2014 May;66(5):287-97.
  • 36. Diagnostic Algorithm for nc-MCAS Patient with signs and symptoms of mast cell activation in at least 2 organ systems Consider and rule out other medical disorders that may explain symptoms (eg, carcinoid, pheochromocytoma, gastrinoma, VIPoma, porphyria) Evaluate for mast cell clonality (serum tryptase, bone marrow) Classify as MMAS or SM Treat and monitor Yes Evaluate for mast cell mediators when patient is symptomatic (serum tryptase, N-methylhistamine, PGD2) No Trial of meds to block mast cell mediators, Lifestyle to reduce mast cell activation Trial of meds to block mast cell mediators, Lifestyle to reduce mast cell activation Positive Negative Likely nc-MCAS, keep treating, consider alternative Not improved in 3 to 6 months, search for alternative Equivocal responseGood response Good response May have nc-MCAS, keep treating, consider alternative Has nc-MCAS, keep treating, and monitor Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18. Flow diagram slightly modified to include lifestyle-based therapies.
  • 37. When to Suspect MCAS • Patient presents with a chronic (persistent or recurrent), waxing and waning or slowly progressive multisystem polymorbidity that is generally, but not necessarily, presents in a context of underlying chronic inflammation. • Syndrome usually acquired early in life via interaction of environmental factors with heritable risk factors. • Virtually all of the syndrome’s manifestations are non-specific, leading to decades of unexplained illness and incorrect diagnoses that poorly respond to empiric therapies. • Systemic MC disease of any form is not presently curable. The aim of therapy is to control symptoms through trigger avoidance, diet , lifestyle, supplements, and medications. • Once MCAS suspected, a methodical, persistent trial-and-error approach usually leads to helpful therapy. Molderings GJ, Afrin LB, et al. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology and Oncology. 2011;4:10-29. History
  • 38. When to Suspect MCAS • Skin: flushing, urticaria, pruritis, dermatographism, urticaria pigmentosa, angioedema, eczema. • Gastrointestinal: abdominal pain, cramping, diarrhea, gas, bloating, reflux. • Pulmonary: cough, wheezing, air hunger, shortness of breath. • Upper Respiratory: nasal congestion, throat itching, soreness, or swelling. • Cardiovascular: fatigue, rapid heart rate, low blood pressure, fainting, near- fainting. • Neurological: headaches, difficulty concentrating, anxiety, irritability, fainting, near fainting. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Current Allergy and Asthma Reports. 2013 Feb;13(1):10-18. Flow diagram slightly modified to include lifestyle-based therapies. Common Signs and Symptoms
  • 39. Alvarez-Twose I, et al. Clinical, biological, and molecular characteristics of of clonal mast cell disorders presenting with systemic mast cell activation symptoms. Journal of Allergy and Clinical Immunology. 2010 Jun;125(6):1269-1278. Predictors of clonal MCAS • Male gender • Absence of urticaria or angioedema • Absence of near-fainting or fainting • Serum total tryptase level >25 ng/mL Bone marrow biopsy should be considered in patients with a serum total tryptase >20 ng/mL, or >11.4 ng/mL in patients with a history of significant blood pressure drops or fainting.
  • 40. Treatment for MCAS Avoid Known Triggers • Temperature extremes, sunlight • Mechanical irritation • Alcohol, illicit drugs • High histamine foods, food additives • Stress • Certain anesthetic agents • Environmental biotoxins or man-made chemicals
  • 41. Treatment for MCAS Medications • H1-histamine receptor antagonists (diphenhydramine, hydroxyzine, cetirizine, fexofenadine) • H2-histamine receptor antagonists (ranitidine, famotidine) • Mast cell stabilizers (NasalCrom, GastroCrom) • Leukotriene inhibitor (Singulair, montelukast)
  • 42. Treatment for MCAS Supplements that Often Help • Neuroprotek (quercetin, rutin, luteolin) Algonot • Histamine Block (diamine oxidase)* Seeking Health • ProBiota (may reduce histamine in some people) Seeking Health • Natural D-Hist (vit C, quercetin, nettles, bromelain, NAC) Orthomolecular • Quercetin + C (from Saphora japonica and sago palm) TwinLabs • Mangosteen (lowers histamine and prostaglandins) Source Naturals * Use with caution if allergic to pork
  • 43. Diet and Nutrition in the Treatment of Mast Cell Disorders Helpful Nutrients Helpful Foods* Harmful foods antioxidants fresh fruits oxidized foods (fried, smoked) bioflavonoids fresh vegetables processed foods natural antihistamines legumes (beans) foods with additives omega 3 fatty acids fresh meats and fish fermented foods mangosteen most leafy herbs high histamine foods** *Some persons may not tolerate helpful foods due to other types of reactivity. **Highly aggressive restriction of histamine-containing foods may be counterproductive. The body needs histamine and may induce a compensatory increase in histamine synthesis when histamine support from food is very low.
  • 44. Diet and Nutrition in the Treatment of Mast Cell Disorders Some high histamine foods pickles seeds beer mayonnaise nuts wine sauerkraut chocolate champagne vinegar cocoa shellfish dried fruits processed meats tofu cheese yeast canned vegetables mushrooms food additives egg whites aged cheeses tomatoes spices spinach Keep meats and fish refrigerated! Eating meat or fish left out too long can cause histamine poisoning!
  • 45. Diet and Nutrition in the Treatment of Mast Cell Disorders Some foods with anti-histamine effects • Apples: rich in quercitin • Carrots: rich in vitamin A • Watercress: inhibits histamine release • Broccoli: H2 receptor antagonist • Ginger: H2 receptor antagonist • Thyme: anaphylaxis inhibitor • Fennel: antioxidants, antihistamine, anti-inflammatory • Turmeric: stabilizes mast cells, inhibits histamine release Visit www.lowhistaminechef.com to access some of the best information available on moderating mast cell activation through lifestyle change.
  • 46. Diet and Nutrition in the Treatment of Mast Cell Disorders You can’t avoid histamine containing foods while on an otherwise toxic diet and expect to be well. The body works in conjunction with thousands of plant-based nutrients. If a low-histamine diet works it is in large part due to the multiple anti-inflammatory effects of whole foods. - Dr. Joel Fuhrman (food micronutrient expert) On low-histamine diets I don’t believe that any food list can address the mystery and beauty of nature, the body’s relationship to this mystery, or the power of our minds to make us sick or well. Histamine-lowering foods work only when accompanied by an anti-inflammatory diet rich in whole foods, and a healthy, stress-reducing mind-body lifestyle. - Yasmina Ykelenstam (The Low Histamine Chef)
  • 47. Patient-centered systems medicine. 15 N. Prospect Park Ridge, IL 60068 847-232-9800 www.parkridgemultimed.com