In non allergy mast cell disease, mast cells are split easily by various mechanisms, but NOT IgE (see "Mast Cells and Triggers").
Mast cells release chemicals. These chemicals attach to receptors on cells, and when the chemical attaches, it sends a signal to the cell. Imagine thousands of cells doing the same thing at the same time; this cascade of signaling causes symptoms.
Here are the symptoms by the chemical released. All symptoms can occur daily or in an anaphylaxis .
if you are completely new to Mast cells -You may find the normal mast cell page useful ;-)
Some of us wake up one day and BAM, we have symptoms .In others symptoms get worse at a certain point but on looking back you can see times when you had smilar symptoms before . Some of us have our symptoms and conditions evolve over several years .
Some of us shock-Anapahylaxis and have no symptoms in between
Some of us have daily symptoms but never shock
Some of us do both
Histamine , PAF , leuoctrines and compliment make blood vessels porus . This is a problem.
In the body fluids are stored in 3 places - In the blood , Inside cells (intercellular ) and in the space between the cells (extracellular ). normally these fluids are kept in the same volumes by homeostais - GCSE biology here - were fluids move accross mebranes in both directions to maintain balance .
So now- histamine has made our blood vessels porus allowing protiens and fluid out of the blood into the space between the tissues. This is called 3rd spacing and leads to 2 things
1) Swelling of these tissues affecting the function of organs
-pelvic organs -pressing on nerves
2) the fluid can't return so there is less circulting fluid in the blood . This makes the body do several things
A) make the heart beat fast to get the lesser volume to the lungs to get oxygen and to the tissues
B) Makes the body put blood pressure up for a short time . This pushes all the blood in the edges( periperies) into the middle to make sure organs get enough blood .
C) When too much fluid has gone the heart doesnt get enough oxygen so goes slow
D) Blood pressure drops below 90 top figure ,
C&D lead to unconciousness and if not treated death - See Anapahylaxis
2-4 days later this fluid in the tissues is drained back into the circulation by the lymphatic system- a second fluid system which has nodes were fluid from the tissues collects then is moved back into the bloos. This then goes to the kidneys and the body knows this fluid has been replaced, so passes it as urine
Those of us with daily symptoms are losing fluid at a slower rate all the time - so - need to replace fluids so they dont get the serious symptoms .
This diagram shows the lymph ducts which drain into the blood at various points around the body .
So fluid leaves our blood and becomes interstitial fluid-extracellualr fluid - this drains into lumphatic vessels . It is moved along by small contractions or by muscles pressing on them .
On itsjourney the fluid passes through lymph nodes (diagram 2) were it is met by many immune cells which it.passes through so any bacteria or cancer cells are found the body initiiates an immune response and deals with it .
Also all over the body there are areas of lymphoid follicles known as the mucosa-associated lymphoid tissue (MALT). Which filters lymph in a smsilar manner to lymph nodes
It then, via lymph ducts drains back into the blood as shown in diagram 3.
The lymphatic system also acts as the transport system for immune cells between the bone marrow were they begin life and to the spleen
On a more personal note ......... Although I felt my symptoms all began July 18th 2008 . In hindsight I now know I had symptoms over several years. Stabbing abdominal pains as a teenager, loss of appietite , funny bad throat feeling and blocked nose that never turned into a cold . Swollen stomach randomly every 6 months. In the year proceding me "getting ill" I had a strange asthma that wasnt quite asthma event, a headache so bad it was thoought it might be a brain bleed, it wasnt, swollen stomach with all the symptoms . When it began properly nothing really made sense and I went round different specilaites as different symptoms emerged . This took me to Decmeber when I had my first recognised biggie-anaphylaxis . In talking with others I have found siliarities in symptoms and some real contradictions . Like i sit under afan 24/7 but a mast cell freind feels the cold. Its important we dont make comparisons and feel like this cant be us or that one person is iller than another . Just we are a group of people with a group of conditions which involve mast cells so we should expect differences but we have many similarities .
Over these 4 years I have found my symptoms vary in how they present. I have fast reaction, medium, slow and slow burn. This depends on trigger and amount of trigger encountered. This is different to how True allergy anaphylaxis presents which is always fast everytime .
Fast reactions are 0-100 in terms of symptoms severity in 3 minutes maximum . This is my anaphylaxis
Medium - were I have building symptoms for half an hour then go fast into an anaphylaxis
Slow were ill have symptoms-stop them with antihistamines but when they wear off 3-6hrs later I go into afull raction
Slow burn - Which is were I have symptoms but they don't become serious but continue for days or weeks
The fact I needed to drink so much to remain feeling well was something I noticed quickly in all of this. I did not undertsnad exactly why. Now I know in the moment - I lose fluid and also histamine - makes my heart beat faster taking more blood to my kidneys which makes me produce more urine -which makes me further dehydrated . Secondly prostoglandins open my blood vessel in my kidneys bringing the maximum amount of blood to be flitered = even more urine= even more dehydrated . These things happen wether I have an epipen or not .
It is known that Anapahylaxis lets albumin out of our blood into our urine , which is protien -which is wouldnt normally do .
This happens in all of us in a full reaction becuase those blood vessels are porus, letting through protiens which they normally wouldn't .
In a biggie I feel suddenly so thirsty. i need to drink at least alitre steright to quench the thirst-so my body is good at telling me something is going on . With that litre I take some antihistamines ( see anaphylaxis page ) .
Day to day my histamine and prostoglandins are making me pass high volumes of urine and the 3rd spacing is going along more slowly than in a biggie .But I ma still losing fluid .
Most days I drink 5litres through the day to maintain my hydration. Signs this is getting low are
- double brething like when your upset
-My blood pressure changing quickly when I stand up, making me jiddery inside or my chin shaking to whole body shakes
My Blood pressure goes up first=headache and feelinga bit weird-not lightheaded just weird -Then drops within 2 mins .
I can drink myself out of this sitaution . If I am sjaking I require an antihistamine as well
IF I AM FEELING UNWELL I TAKE MY EPIPEN .This is not an alternative but a way to mange your fluid needs day to day ;-)
Separate from the chemicals from mast cells directly
Compliment – Your inborn immunity – gets activated and has consequences
Smooth muscle spasms – digestive tract , bladder , reproduction system , chest wall , Throat
Blood vessels become porus leaking fluid into tissues – note 2l can move before swelling becomes visable .
Activates mast cells
Every patient is individual in their symptoms but have similaraties .
Swelling of airways and all over
- By increasing microvascular permeability ( Makes blood vessels leaky allowing fluid out =swelling )
Asthma type symptoms
-- mucus secretion in airways.
Enhance growth of human airway epithelial cells,
Causes contraction of smooth muscle - airways
Also stomach, bowel ,bladder and womb spasms
Inflammation all over the body -airways, bowels ,stomach well documented
- Fat balance ( 7)
- platelet activating factor (PAF) induced shock - see mast cells
- Reduce myocardial contractility and coronary blood flow ( reduced heart contraction strength and blood flow to the heart muscle - putting heart at risk of not having enough blood going to it
- Induce long lasting hypotension ( low Blood pressure
- Stimulate angiogenesis.- The physiological process involving the growth of new blood vessels from pre-existing vessels - which is essensial for healing
Opens up blood vessels- vasodilation -bringing it close to the surface and making it so the heart doesnt have to pump as hard - which gives lower blood pressure
Flushing of skin
Airway spasm -wheezing
Headaches ( from blood vessels opening , dilating in an enclosed space )
Smooth muscle spasms - bowel , stomach , throat , bowel , bladder , womb
BP drop-from blood vessels opening
Anxiety when you don't feel anxious , sometimes pacing. Over time can lead to depression .
Brain receptor histamine effects - receptors 1&4
Pins and needles / numbness – parathsesias
– hands ,arms ,feet , to numbness
Nerve pain – neurogenic
– Hands , feet , abdomen ( stabbing ) – from histamine neurotransmitter role
Brain fog - mixed organic brain syndrome
Histamine recptors in the temporal lobe
– conentration poor ,
- memory poor,
- agitation ,from grumpy to rages
- word finding problems ,
- down thoughts
Heat centre has type 4 receptors as well as type 1, some some heat can be controlled .
Histamine receptor 2 symptoms - digestive tract - Mouth to bottom
Abdominal pain – from swelling bowel , cramps , on left or right side and over liver ( right side under ribs )
Bowel swelling - frim the submuclasal layer swelling - angiodeama causing pain , large , hard abdomen
Diarrhea -from histamine and serotonin
Sudden for many hrs
– or loose stools , pencil thin stools and apparent consipation were the bowel swells closed .
Urgency and frequency
Nausea - feeling sick - from incresed stomach acid (img 3 ) shows how histmine affects histamine type 2 recptors in the stomach wall .
Vomiting - from stomach muscle spasms expelling contents upwards. From complete stomach contents to small vomits when throat is restricted
GERD -Reflux (acid indigestion /heartburn) -from stoch acid leaking inot the oesphegus causing inflammtion
++++++ Too much stomach acid
Spasms of - smooth muscles - in waves or singlar spasms - causing pain.
Bladder - making you feel like you have an infection when you don't have one - Intersitial cystitis
Bowel , stomach ,
Womb , with or without bleeding
Chest wall and restricting narrowing airways and
- giving anxious appearing breathing
Short of breath –
begins with not being able to take a deep breath
- From mildly wheezy to a wheeze audible accross the room.
- Due to histamine causing
- Muscle constriction around individual airways - closing the space inside -bronconstariction
- Increased mucous production
-Causing wheezing on breathing out and hyperextended lungs on chest xray
- Making breathing rate -Increase so you can't speak a whole sentace between breaths - of 40 - very fast
- lungs full of fluid- Pulmonary odeama . From fluid leaking out of the blood vessels into the end point of the lung tubes -alvioli
Histamine makes bloods vessel leaky
Fluid leaks out = swelling-angiodeama internal (as well as skin )
Dizzy - At rest or on movement ( pre syncope ) is because there is too little fluid left circulating. ( see 3rd spacing below )
Your body compensates with high BP for a short time
Then - BP drop - feels like light headed, spinning or passing out .
Fast heart – like your heart banging out of your chest in response to the low blood pressure to get the blood around quickly
Also histamine working directly on the heart making it beat faster
The histamine is produced there and travels there in the blood .
Img 1 - shows vasodilation -relaxing of blood vessel walls and incresaed vascualr permability = spaces open for big cells -protiens to get through - water, blood cells which are looking for bugs to rid the body of , alubulmin -protien .
Swelling - Angiodeama - arises from fluid moving into tissues – by blood vessels being made Porous allowing fluid to move -
- 2l can move before you can see it
- can be anywere internal or external
- can be just on one side of the face or body
Histamine has 4 receptors (see "Subpage"). There are medications to block 2.
Histamine receptor, type 1, affects: receptors in skin, lungs, bladder, womb, eyes, ears, heart, blood vessels, nervous system, brain, and brain linings.
Itching: Because histamine irritates nerve endings
Skin writing: dermatographia
Urticaria: Hives /Wheal - big red lump with a red area around it or raised area
Burning rashes: akin to instant sunburn/ nettle rash
Flushing: Red skin, typically on face neck and torso;
this is DRY (not pouring with sweat)
until BP goes low: shock, then
cold clammy sweating.
The defining features of Angiodeama and Urticaria
Symptoms and signs of angioedema may vary slightly between the different types of angioedema
Heriditory, autoimmune or histamine based, but in general, some or all of the following occur:
Marked swelling, usually around the eyes and mouth
Throat, tongue, hands, feet and/or genitals may be affected too
Skin may appear normal, i.e. no hives or other rash
Swellings may or may not be itchy
Swellings may be painful, tender or burning
In severe angioedema, swelling of the throat and/or tongue
may make it difficult to breathe
Swelling of the lining of the intestinal tracts may cause
gastrointestinal pain and cramps
Adapated from : Kaplan AP, Greaves MW. (see "Doctors' details") Angioedema. J Am Acad Dermatol 2005;53:373-88.
So with histamine being constantly released from mast cells by triggers -These things are happening at a low to a serious level -
You want to walk and move about - so you have faster heart as it works harder to help you breathe well .
This is were the medications come in
Deep inside the bones described as burning . The exact cause is unknown. But is felt to be due to mast cells replacing osteocytes-bone cells . This pain is expereinced in all mast cell patients .research is currently ongoing . Mast cells begin their life in bone marrow .
Common in long bones and joints .
Also in ribs -which is painful on breathing
partial causes in head pain
can be in any joint bone
also inflammation of cartilage -observed in many patients as intercostal pain-in between ribs . In mast cell ribs also have a honeycomb appearance
Joints also have mast cells -The histamine causes-inflammation and swelling .
Can be very very painful
Over heating - which feels like burning inside your body . In tissues and in the blood . Sometimes accompanied with redness and swelling or without
This happens for several reasons -
Histamine works on the heat centre in the brain- In the temporal lobe
TNFa resets the temperture point in the hypothalamus .(In the brain )
2 other cytokines are pyrogenic-causing tempertures
This is noticable very quickly
- when out of cool air. and/or
- ambient temperture is over 20oc
Poor cold tolerence -especially if temperture changes suddenly
Upper airway symptoms
Intolernece of smells - leading to vomiting
Histamine causes -
Increased mucous production
Swelling in enclosed spaces ( nose sinus' , mouth and throat
Pain from swelling pressing on nerves
Throat close – from swelling inside the throat tissues
From it feeling tight ,
Voice dropping low (Video 2 )
To coughing a bit to cloughing a lot
To completely closed ( leading to not breathing , collapse ( anaphylaxis symptom )
Stridor - press link button for example
Eyes have mast cells on the surface - on the conjunivita . Releasing histamine
Itching and ,
inflammation- redness ,swelling and soreness
Angiodeama can swell the tissue surrounding the eyes -
From histamine from eye mast cells
-spasms of eye lids and eye muscles can occur . because the eye muscles have histamine recptors
Ringing ears - Tinitus either constant or varying , is a Sign of high overall inflammation.
-swelling pressing on nerves
-Histamines causing irirtaion and pain in nerves
The eustation tube is connected to the throat -so itching ears are connected with viocebox ( larnageal swelling
Swelling ( angiodeama) and red outer ears are common . This can be one side only( asymetrical ) ,which is more common , speading accross the face or symetrical .
Sleep and wakefulness
Central nervous system -modulate circadian cycle
When histamine itself binds to H1 receptors, it activates a G-protein-linked second messenger system that activates phosphatidylinositol and the transcription factor cFOS, resulting in wakefulness, normal alertness, and pro-cognitive actions.1,5,19-21
Histamine neurons control sleep
Histamine H1 receptors are activated by endogenous histamine, which is released by neurons that have their cell bodies in the tuberomammillary nucleus of the hypothalamus.
Become active (Highest ) In wake cycle (2HZ)
slow wave sleep (0.5)-Stages 3-4
REM sleep -No firing
When hisatmine attches to h1 recptors in the cortex -increasing the exictory volatage -produced by a excitory( stulating nerve to fire -releasing histamine ) current .
H1 blockers cause drowsiness by opposing this action
So in mast cell with all the extra histamine- The nerves h1 receptors will be constantly stimulated - leading to wakefulness at night . Also no rem sleep
Tryptase stops HDL the good cholesterol soaking up bad cholesterol on cell membranes . making cholesterol high .
It is also involved in insulin resistance as is TNF@ which leads to high carbohydrate cholesterol -Triglycerides and makes type 2 diabetes more likley .
High LDL leads to build up of fats in the artery walls . mast cell tryptase is involved to breaking the caps of these buildups -which causes heart attacks (MI ) .This happens over many years
High cholesterol without other known causes should have mast cell conditions considered as the cause ( )
Fatigue is an inadequate term-exhaustion on every level-physical, mental and emotional is better.
Most pts need to sleep for 14hrs aday with naps on top . This can be constant and/ or sudden leading to making even holding you head up impossible . Arms unable to hold even a mobile phone, shaking, dropping things .
The cause seems to be due to many factors - the bodys level of work , poor sleep, pain, swelling, breathing difficlaties. be awoken by a 2am histamine release .
Many report sudden fatigue in response to triggers.
Mouth symptoms can be "geographic tounge " sore with patches .Mouth ulcersseemingly from no where. Bleeding gums ,geberal mouth swelling and swelling of tounge, inside cheeks, uvula and back of throat .
Gums contain many mast cells so brushing teeth or eating crunchy foods can bring bleeding ( from heparin ) swelling and systemic flushing .
Mouth symptoms can also reflect symptoms through the digestive tract -as its the "same skin" .It is well documanted that mouth ulcers are present in inflammatory bowel disease. The mast cell contents cause inflammation in the mouth and through the digestive system -in mast cell -in the absance of bacteria or virus'
Oral thrush is common . See treatments
blood thinner so leads to bleeds
- womb - patieche , between cycle bleeds should ALWAYS be investigated
- bowel - Bowel bleeding shouls ALWAYS be investigated
Oesteoprosis- High heparin we conclude that heparin decreases trabecularbone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption.
Add in the effects of IL6 and TNFalpha and heparin receptor 3 release of clacium from cells and poor absrbtion of vitamin d and clacium from the digestive tract-all accumaltes to making osteoprosis a known side effect of mast cell disease a real issue .
EVERY mast cell patient should have base line Bone density scan
Bone density scan in diagnosos of osteoprosis . Bone density is measured by an extrenal scan which is painless. The information is processed according to age and gender and results come back for hips and spine .
Its its important to get a baseline as soon as possible even in skin only mastocytosis as these patients often have this neglected and they are then not on treatments to reduce bone loss and clacium and vitamin d supplements
Heparin from mast cells becomes Bradykinin -which causes low blood pressure (hypotension )and swelling ( (o)edeama ) . Also t cells being attracted and adhering causing more immune system actions .
Bradykinin also activates Phospholipidase A2
Phospholipases A2 (PLA2s) EC 220.127.116.11 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids. Upon downstream modification by cyclooxygenases, arachidonic acid is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes, which are categorized as inflammatory mediators.
Serotonin has several roles and effects in the body
- Regulation of bowel movements by incresing smooth muscle tone .
- Regulates insulin and growth factor release - so suppresses insulin release from the pancreas
- Breathing rate (more=higher rate )
- heart rate (more = higher rate )
-Constricts blood vessels -vasoconstriction which means the heart has to pump harder (increased cardiac output ) this increases blood pressure
- a neurotransmitter
- activates cells ( with recptors )
- upregulates any mood - anxiety , depression, happy , angry - making it more intense .
- Controls sleep
- has role in building and degerating bone
-In plateletts - heomostatis and clotting
High levels lead to serotonin syndrome -see images
Mangement in image -
Low-depression -Note mast cells can have low serotonin with no depression -see big change
Low serotonin - is not common in mast cell patients . Those who do may or my not have a clinical depression .
See Medicines -depression and anxiety for treatments within a mast cell context and Big chnage for the many factors which impact your life in mast cell .
The sedative effects of antihistamines is worst if you take them -then engage in a cognitive activity -Maths, spelling, driving.
This effect had been reported to me by mums of mast cell children .
The picture above shows decreased areas of activity in the areas of the brann were cognitive processing occurs following antihistamines and a cognitive activity.
Many mast cell patients don't expereince drowsiness at all with "drowsy" antihistamines . Day or night
Suggesting that the brain histamine recptors are not completely saturated due to high histamine levels .
This benefits patients in symptoms being controlled without daytime drowsiness with the antihistamines which cross the blood brain barrier - hydroxyzine , chlorphenamine mealate and
Brain fog ......................The reality
Its like being a goldfish with demetia also feeling spearated from everything around you
I call it monosyabllic moron mode - I can't think of asimple word that I use everyday ..................... soon after ill begin flushing
It can also make me very confussed. Not understanding converstaions .I can get grumpy to full on angry . if I hang up the phone on someone within 2 minutes more symptoms will come .
Before meds controlled it . I couldn't concerntrate on anything and its like thinking thorugh a fog .
If im building up to areaction my concentration will go. My classic is pickinga tv channel then forgetting what I picked because its still in the ads ( within a minute ) or 30 seconds into the ad break forgetting what I have been watching.
I have begun repeating myself in converstaions , after about 2 hrs, so not too bad yet, but its noticable .
My longterm memory is intact
Brain fog is a symptom of a number of conditions .
REM -rapid eye movement sleep is the rejuvinating sleep. Without it the person will wake exhuasted .
One of the hallmarks of rem sleep is parlysis - laying completely still .This allows the muscles to rejuvenate and process toxins allowing full function on waking. So no REM sleep leads to physical exhastion akin to running a marathon over time .
Nightime waking is seen in mast cell pts due to other chemical also disrupting rem sleep .
Alongside histamine, leucotrines , Il1 and tnfalpha also disrupt rem sleep
Bowel swelling and inflammation
The submucosal layer of the bowel swells with fluid leaking from the blood vessels .
This leads to stools being thin or the bowel closing completely .
Inflammation -causes redness and damage to the bowel lining . Further reducing the size of the inside of the bowel .This can lead to mucous stools .
Stools can also be yellow . If stools are green then infections should be suspected.
Histamine Receptor 2
Stomach acid level - Stomach acid level is normally controlled by neurotransmitters -which stimulate goblet cells to produce gastrin -which tells entrocromaffin type cells to make histamine - which tell the acid producing cells to make acid.
We have too much histamine -Why ?
We have mast cells in the stomach wall
Somastatain -which is produced from d cells in the stomach wall is a known mast cell activator .
We also know stress - in particular substance p and CRH also cause mast cells to spill contents
Histamine which we know is a chemical constantly released .
We can also have high gastrin - which stimaultes the entrocromaffin like cells to produce histamine .
It is high because mast cell histamine also stimulates production of gastrin.
Gastrin affect enrocrommafin type cells and acid producing cells directly .
High acid leads to heart burn , reflux -gastro osphegeal reflux -which burns the oesphegus .
At also causes nausea which can be constant and like glass in your stomach
More mucous and Inflammation prevent air reaching the alveoli were gas exchange happens .
Gas exchange - in the avioli
The gasses in the air-oxygen, carbon dioxide , nitrogen etc move into and out of the air sacs into/out of the blood.This allows oxygen to move into the blood and for carbon dioxide to move out and be expelled when breathing out
These factors = low oxygen levels in the blood .
Organs can cope for ashort time without oxygen -except the brain which needs it for all functions .
This leads to the symptoms -
going vauge / loss of conciousness
Muscle spasm -of smooth muscles
The bowel has smooth muscles .This spasm /cramp causes diarrhoea and variable stools-pencil thin ( due to swelling ) .The staomch also has smooth muscles -leading to vomiting .
Womb - spasms are also coupled with bleeding -called peteichie
ANY bleeding should be investigated.
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Uritciarias can be acute or chronic - below 6 weeks duration is seen as actute longer is chronic .
20% of the pouplation worldwide have a uritcaria in thier lifetime . 1% have chrnic urticaria of some kind ( Greaves 2007) . For more details on these see the mast cell conditions page .
In real terms these are hives or rashes from in one location to body wide .
These have certain features -
- they are on the skin surface - in the dermis and epidermis
- They cause redness , itching and sweling .
- They can occur due to heat , cold, vibrtaion -physical
- Pressure -from simple things like clothing ,holding bags
- Stress -CRH & emotional times - cholinergic - due to acetylcholine release affecting mast cells
- Autoimmune - 15-17 % have thyriod antibodies -with or without active thyriod disease ( Greaves etal 2007 )
or unknown - and after testing idiopathic
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Headaches -up to migraines inc occular migraines are histamine driven .
Stress is proven to cuase migraines . Its hormone crh and uroocrtine both activae mast cells in the brain linings -dura .
The chemicals relased make the blood vessels leaky as we know of elsewere .
This breaks what is called the blood brain barrier . Tnf alpha is heavily involved in this .
This leads to a number of effects inc increased mast cells traveling into the brain .
This alongside fluid moving into the tissues and blood vessels opening ( prostoglandins ) and bone pain makes for chalenging migraines .
There are also recnt reports of connections being made between these mechnaisms and brain inflammtion called encephelitis . I will come back with more details x