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The Pivotal Role of Histamine inthe Symptoms of Food
Intolerance
Janice M. Joneja,Janice M. Joneja, PhPh.D..D.
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Histamine in Food Allergy
Traditionally, allergy is defined as a Type ITraditionally, allergy is defined as a Type Ihypersensitivity (IgEhypersensitivity (IgE--mediated) reactionmediated) reaction
Histamine is the most important inflammatoryHistamine is the most important inflammatory
mediator in IgEmediator in IgE--mediated reactionsmediated reactions
Principally released from mast cellsPrincipally released from mast cells
Also released by degranulation of otherAlso released by degranulation of othergranulocytes especially basophilsgranulocytes especially basophils
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Histamine in Non-IgE-mediated Reactions
IgGIgG--mediated reactions also releasemediated reactions also release
histaminehistamine FoodFood--specific antibodyspecific antibody--antigen complex formedantigen complex formed
Activates complement cascadeActivates complement cascade
Production ofProduction of anaphylatoxinsanaphylatoxins (C3a; C5a)(C3a; C5a)
Action ofAction of anaphylatoxinsanaphylatoxins on mast cells releaseson mast cells releases
histaminehistamine and other inflammatory mediatorsand other inflammatory mediators
Reaction is delayed in onset (up to 8 hours)Reaction is delayed in onset (up to 8 hours)compared to IgEcompared to IgE--mediated immediatemediated immediate
reactionreaction
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Action of Histamine in Allergy VasodilationVasodilation: widening of blood vessels: widening of blood vessels
May cause slight drop in blood pressureMay cause slight drop in blood pressure Increase in heart rateIncrease in heart rate
ErythemaErythema
Flushing, reddeningFlushing, reddening
Increased vascular permeabilityIncreased vascular permeability
Fluid moves from blood vessels into tissuesFluid moves from blood vessels into tissues Causes swellingCauses swelling
PruritusPruritus
Histamine is the main cause of itchingHistamine is the main cause of itching
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Examples of Symptoms of Food
Allergy
Urticaria and angioedemaUrticaria and angioedema RhinoconjunctivitisRhinoconjunctivitis andand rhinorrhearhinorrhea
HeadachesHeadaches
Symptoms in the oral cavitySymptoms in the oral cavity
Digestive tract disturbances: abdominal pain,Digestive tract disturbances: abdominal pain,
diarrhea, nausea, vomitingdiarrhea, nausea, vomiting Similar symptoms can be caused bySimilar symptoms can be caused byhistamine intolerancehistamine intolerance
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Food Allergy and Food Intolerance:
What is the Difference?
Definitions:Definitions: Food Allergy:Food Allergy:
A response of the immune system involvingA response of the immune system involving
antigen consisting of protein or a moleculeantigen consisting of protein or a moleculelinked to a proteinlinked to a protein
Food IntoleranceFood Intolerance
A nonA non--immunologically mediated event,immunologically mediated event,usually triggered by small molecular weightusually triggered by small molecular weight
chemical substances, and biologically activechemical substances, and biologically active
components of foodscomponents of foods
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Characteristics of Food Allergy
and Food Intolerance
Food allergy:Food allergy: Requires a Requires a sensitizingsensitizing event that primes theevent that primes the
immune system for future responseimmune system for future response
Reaction is not doseReaction is not dose--dependentdependent Allergic potential is an inherited characteristicAllergic potential is an inherited characteristic
(is idiosyncratic)(is idiosyncratic)
Food IntoleranceFood Intolerance Does not require primingDoes not require priming
Event is doseEvent is dose--dependentdependent
Reaction is not always idiosyncraticReaction is not always idiosyncratic
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Histamine Intolerance
Histamine is a biologically activeHistamine is a biologically activederivative of an amino acid (histidine)derivative of an amino acid (histidine)
Is present in many foods and beveragesIs present in many foods and beverages
High doses are toxic to all humans:High doses are toxic to all humans:
levels of >2.7 mg/kg body weight causelevels of >2.7 mg/kg body weight cause
histamine poisoninghistamine poisoning
Individual tolerance determinesIndividual tolerance determines
reactivity to small quantitiesreactivity to small quantities
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Individual Intolerance of
Histamine
Cause is most likely a defect in theCause is most likely a defect in the
catabolism of histaminecatabolism of histamine
In humans, enzymatic inactivation ofIn humans, enzymatic inactivation ofhistamine occurs by two pathways:histamine occurs by two pathways:
Diamine oxidase (DAO)Diamine oxidase (DAO) Histamine NHistamine N--methyl transferase (HMT)methyl transferase (HMT)
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Theory of Histamine Excess Histamine from dietary sources andHistamine from dietary sources and
from the activity of intestinal microfrom the activity of intestinal micro--organisms will normally beorganisms will normally be catabolizedcatabolized
before gaining access to circulationbefore gaining access to circulation If enzyme activity is reduced, histamineIf enzyme activity is reduced, histamine
will gain access to blood and augmentwill gain access to blood and augment
the level of plasma histamine fromthe level of plasma histamine from
endogenous sourcesendogenous sources
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Histamine-restricted Diet:
Case studies - Subject #1
Female aged 24 years; cashier and studentFemale aged 24 years; cashier and student PresentingPresenting SxSx::
RecurrentRecurrent urticariaurticaria on neck, midsection,on neck, midsection,
back, arms: Hives occur on various bodyback, arms: Hives occur on various body
surfaces several times a week; present forsurfaces several times a week; present for
several yearsseveral years
DermatographiaDermatographia and pressureand pressure urticariaurticaria
(water in shower)(water in shower)
Frequent headaches: occur almost dailyFrequent headaches: occur almost daily
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Histamine-restricted Diet:
Case studies - Subject #1
Other relevant data:Other relevant data: SeasonalSeasonal rhinoconjunctivitisrhinoconjunctivitis
Borderline asthmatic (especially in smokyBorderline asthmatic (especially in smoky
environment)environment)
SkinSkin--test positive to: dust, grasses, trees,test positive to: dust, grasses, trees,
feathersfeathers Respiratory tractRespiratory tract SxSx improved when livingimproved when living
in a home with hardin a home with hard--wood floorswood floors
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Histamine-restricted Diet:
Case studies - Subject #1
Outcome of histamineOutcome of histamine--restricted diet:restricted diet: UrticariaUrticaria andand prurituspruritus completely clearedcompletely cleared
upup
Patient experienced only one headachePatient experienced only one headache
during the diet trialduring the diet trial -- following consumptionfollowing consumption
of tomato soupof tomato soup
Consumption of Tylenol for control ofConsumption of Tylenol for control of
headaches reduced from daily to only onceheadaches reduced from daily to only once
(after above episode)(after above episode)
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Histamine-restricted Diet:
Case studies - Subject #2
Female, age 29 years. Case room nurseFemale, age 29 years. Case room nurse PresentingPresenting SxSx::
UrticariaUrticaria
FrequentFrequent diarrheadiarrhea and vomiting after eatingand vomiting after eating
certain meals since childhood, and morecertain meals since childhood, and more
severely since her latest pregnancyseverely since her latest pregnancy Migraine headachesMigraine headaches
Panic attacksPanic attacks
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Histamine-restricted Diet:
Case studies - Subject #2
Other relevant dataOther relevant data::
SkinSkin--testing in childhood resulted in wholetesting in childhood resulted in whole
arm swelled to an enormous sizearm swelled to an enormous size
All reactions have worsened since the birth ofAll reactions have worsened since the birth of
her daughter 1 year agoher daughter 1 year ago
Panic attacks becoming debilitatingPanic attacks becoming debilitating
Outcome of histamineOutcome of histamine--restricted dietrestricted diet:: Significant improvement in all symptomsSignificant improvement in all symptoms
Complete remission of symptoms associatedComplete remission of symptoms associated
with panic attackwith panic attack
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Indicators of Possible Histamine
Intolerance Skin tests:Skin tests:
Mildly positive to multiple allergensMildly positive to multiple allergens Large reaction wheal to histamine controlLarge reaction wheal to histamine control
DermatographiaDermatographia
Unusually sensitive to alcoholic beveragesUnusually sensitive to alcoholic beverages
Sensitive to fermented foods, especiallySensitive to fermented foods, especially
Oriental food, cheese, vinegarOriental food, cheese, vinegar Sensitive to benzoateSensitive to benzoate--containing foods,containing foods,
especially cinnamon, green and black teaespecially cinnamon, green and black tea
Positive family historyPositive family history
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Reduced Histamine Catabolism
Indicators of reduced histamine metabolismIndicators of reduced histamine metabolismhave been suggested to behave been suggested to be::
Elevated plasma histamine (>2Elevated plasma histamine (>2 ngng/ml)/ml)
Reduced DAO activity (
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Occurrence of DAO and HMT
DAO occurs predominantly in:DAO occurs predominantly in: intestinal mucosaintestinal mucosa -- kidneykidney
placentaplacenta -- thymusthymus
HMT occurs more widely, in:HMT occurs more widely, in:
brainbrain -- spleenspleen
stomachstomach -- kidneykidney
lunglung -- thymusthymus
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Function of HMT and DAO
HMT primarily functions at the level ofHMT primarily functions at the level ofhistamine receptors:histamine receptors:
It terminates the biological activity ofIt terminates the biological activity of
histamine in a wide range of organshistamine in a wide range of organs The primary function of DAO seems theThe primary function of DAO seems the
elimination of excess histamineelimination of excess histamine
This is effectively achieved in controlling theThis is effectively achieved in controlling theamount of histamine entering the body fromamount of histamine entering the body from
the digestive tractthe digestive tract
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Catabolism of Histamine
Histamine from exogenous sources isHistamine from exogenous sources iscatabolisedcatabolised differently from endogenousdifferently from endogenous
histaminehistamine
Exogenous histamine is metabolisedExogenous histamine is metabolised
predominantly via oxidativepredominantly via oxidative deaminationdeamination byby
DAODAO Endogenous histamine is metabolisedEndogenous histamine is metabolised
more via ring Nmore via ring N--methylationmethylation by histamineby histamine
NN--methyltransferasemethyltransferase
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Catabolism of Histamine (continued)
The two systems produce different endThe two systems produce different end--products:products:
DAO:DAO: imidazoleimidazole compounds:compounds:
imidazoleimidazole--acetaldehydeacetaldehyde
imidazoleimidazole acetic acidacetic acid
HMT: NHMT: N--methylatedmethylated products:products:
NN--methylhistaminemethylhistamine
NN--methylimidazolemethylimidazole acetic acidacetic acid
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Biological Activity of Histamine Breakdown
Products
Biological activity of histamine metabolites isBiological activity of histamine metabolites islargely unknownlargely unknown
It appears that theIt appears that the methylatedmethylated products ofproducts of
HMT activity are inertHMT activity are inert In lab experimentsIn lab experiments imidazoleaceticimidazoleacetic acid (fromacid (from
DAO activity) has been reported to haveDAO activity) has been reported to have
behavioralbehavioral effects in rats and miceeffects in rats and mice
Most do not accumulate, but are excreted inMost do not accumulate, but are excreted in
urineurine
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Fate of Histamine in the Body
Histamine in the blood stream is rapidlyHistamine in the blood stream is rapidlyclearedcleared
May arise from mast cells and basophilsMay arise from mast cells and basophils
In research studiesIn research studies radiolabelledradiolabelled histaminehistamineinjected intravenouslyinjected intravenously
Degradation products can be detected andDegradation products can be detected and
measured in urinemeasured in urine 99% of histamine given orally is prevented99% of histamine given orally is prevented
from reaching the circulationfrom reaching the circulation
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Level of Histamine Metabolites in Urine
Seems to be greatly influenced by:Seems to be greatly influenced by: Level of histamine in foodLevel of histamine in food
Activity of bacteria in the large bowelActivity of bacteria in the large bowel
(caecum and colon)(caecum and colon)
Possibly activity of bacteria in the vaginaPossibly activity of bacteria in the vagina
These are exogenous sourcesThese are exogenous sources The level of endogenous histamine may beThe level of endogenous histamine may be
fairly stable, except when an allergic reactionfairly stable, except when an allergic reaction
causes increased release of histaminecauses increased release of histamine
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Exogenous Sources of Histamine
Amines are produced from amino acids byAmines are produced from amino acids bydecarboxylationdecarboxylation
Result from metabolism of animal, plant, andResult from metabolism of animal, plant, and
microorganismsmicroorganisms Are present in most animal and plant foods inAre present in most animal and plant foods in
small quantitiessmall quantities
Histamine is produced byHistamine is produced by decarboxylationdecarboxylation ofof
histidinehistidine
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Other Food Sources of Histamine
Fermented beveragesFermented beverages
WineWine Beer, ale, lager, etcBeer, ale, lager, etc
Fruits:Fruits:
CitrusCitrus -- Stone fruitsStone fruits -- DatesDates
BerriesBerries -- PineapplePineapple -- CurrantsCurrants
VegetablesVegetables TomatoTomato -- EggplantEggplant -- Soy beanSoy bean
SpinachSpinach -- PumpkinPumpkin -- Red beanRed bean
OlivesOlives
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Other Food Sources of
Histamine
Several species of bacteria in the gut of fishSeveral species of bacteria in the gut of fishand shellfish produce histidine decarboxylaseand shellfish produce histidine decarboxylase
When fish dies bacteria degrade its proteinWhen fish dies bacteria degrade its protein
Bacteria can multiply every 20 minutesBacteria can multiply every 20 minutes Histamine content of ungutted fish can doubleHistamine content of ungutted fish can double
every 20 minutesevery 20 minutes
Shellfish are not gutted before consumptionShellfish are not gutted before consumption LeftLeft--over meats may beover meats may be colonizedcolonized by histidineby histidine
decarboxylasedecarboxylase--producing bacteriaproducing bacteria
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Other Food Sources of Histamine
Some food additives appear to releaseSome food additives appear to release
histamine:histamine:
Tartrazine and otherTartrazine and other azoazo dyesdyes
SulphitesSulphites BenzoatesBenzoates
Some foods contain natural benzoates:Some foods contain natural benzoates:
CinnamonCinnamon -- TeaTea -- BerriesBerries
Egg white (Egg white (ovalbuminovalbumin) has been implicated in) has been implicated in
histamine release by an unknown mechanismhistamine release by an unknown mechanism
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Histidine decarboxylase and the Resident
Micro-flora
Many bacterial species thatMany bacterial species that
colonizecolonize
the largethe large
bowel of humans produce histidinebowel of humans produce histidine
decarboxylasedecarboxylase
Convert histidine in nonConvert histidine in non--digested fooddigested foodmaterial to histaminematerial to histamine
This is an additional source of exogenousThis is an additional source of exogenous
histaminehistamine
If notIf not catabolisedcatabolised by DAO in situ, histamineby DAO in situ, histamine
will enter the blood circulationwill enter the blood circulation
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Inhibitors of DAO and HMT Drugs that inhibit enzymes involved in histamineDrugs that inhibit enzymes involved in histamine
breakdown result in histamine excess:breakdown result in histamine excess:
HMT inhibitors:HMT inhibitors:
AntimalarialAntimalarial drugs (4drugs (4--aminoquinolineaminoquinoline
derivatives)derivatives)
Anticancer drugs (Anticancer drugs (pyrimidine analogspyrimidine analogs))
DAO inhibitors:DAO inhibitors:
CopperCopper--chelatingchelating agents (cyanides;agents (cyanides;carbamatescarbamates))
Carbonyl group reagents (Carbonyl group reagents (aminoguanidineaminoguanidine;;
semicarbazidesemicarbazide))
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Histamine Degrading Bacteria
Certain species of bacteria produceCertain species of bacteria producediamine oxidase:diamine oxidase:
LactobacillusLactobacillus spsp.. -- Sarcina spSarcina sp..
Leuconostoc spLeuconostoc sp.. -- E.E.coli faecium spcoli faecium sp..
Capable of degrading food sources ofCapable of degrading food sources of
histaminehistamine May reduce total histamine loadMay reduce total histamine load
Possible role inPossible role in probioticsprobiotics??