Mastocytosis

Mastocytosis is a recognised diagnosis by the World Health Organisation .

 

The 3  links in yellow are 3 videos on mast cell conditions by the top American Doctors

 

Mastocytosis is a condition where there are extra mast cells in the skin alone or in other places around the body .

 

These trigger easily to triggers

 

When they are triggered - it causes the contents to spill out . This happens to many thousands of mast cells at one time . For more details see triggers and symptoms . The extent of chemical realse can cause anaphylaxis , either typical or atypical in presenataion .

 

All functions within our body are coded in our DNA . This code tells a cell what it is to be and where in the body and all its functions including when to die . In mastocytosis the sequence of chemicals in dna which  tell mast cells to die has been sightly chnaged so the process doesnt happen - hence these cells live forever . This gene is called ckit on codon 816

 

Systemic Mastocytosis definitions . In order for diagnosis the patient needs to have 1 major and 1 minor or 3 minor criteria met.

Major criterion

 

Multifocal dense infiltrates of mast cells (>15 in aggregate) in tryptase-stained biopsy sections of the bone marrow or of another extracutaneous ( other than skin ) organ.

 

Minor criteria

 

1. In biopsy of bone marrow or other extracutaneous organ(s), more than 25% of the mast cells show abnormal morphology (that is, are atypical mast cell type I or are spindle-shaped) in multifocal lesions in histological examination.

2. Detection of a point mutation at codon 816 in the KIT receptor gene. This may

be found in bone marrow, blood or other internal organ.

3. KIT-positive Mast cells in bone marrow, blood, or other internal organs are found to express CD2 and/or CD25.

4. Serum total tryptase level persistently greater than 20 ng/ml. This criterion cannot be used if the patient has a clonal nonmast cell associated hematologic disorder.

 

The presence of one major and one minor criteria or three minor criteria constitute the diagnosis of systemic mastocytosis.

 

Diagnostic techniques differentiate Mastocytosis into the following categories:

 

Cutaneous mastocytosis- is skin mastocytosis

Urticaria pigmentosa (UP) — also known as maculopapular

cutaneous Mastocytosis (MPCM), diffuse cutaneous mastocytosis

(DCM), TEMP , and solitary mastocytoma.

 

It can aslo be in the rest of the body - Systemic

Mast cells can be present in any organ

 

Indolent systemic mastocytotsis

- BMM- Bone marroew only Mastocytosis

- Smoldering

 

Aggressive systemic 3%

- Can progress from indolent but there is no set pattern of occurrence

-  Can be ckit positive or negative

 - Chemotherapy is used –Gleevac is the patient is ckit neg , as it doesn’t work in ckit positive patients . Interferon is used in c kit positive patients

- Mast cell tryptase over 150, would cause high suspicion of aggressive disease

- All other treatments are used to control symptoms

 

In terms of disease progression

- Increased attacks when previously stable , would raise the       question .

- pancytopenia or thrombocytopenia or low WCC but high RBC would raise the question.

- Organs failing indicates smouldering , not enlargement alone . Which raises the question of need for mast cell numbers to be reduced medically

 

Notable facts

- There are mast cell leukemias which can occur (REF)

- Cutanious Mastocytosis can become indolent systemic (REF)- http://informahealthcare.com/doi/abs/10.1080/1042819021000037967

- may have enlarged liver and spleen

- GI tract may be affected

- Mediator release symptoms are common -both daily and  anaphylaxis

- Grade of bone marrow inflatration is “ normally” lower than 5%

- Mast cells co express CD2 and CD25- with kit and contain the kit mutation D816v

- The ckit mutation occurs after conception so is not inherited in systemic Mastocytosis but in uriticaria pigementosa when appearing in children can be passed on.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Mast Cell Conditions

Mast cell activation disorders .

These are new diagnosis’ – monoclonal mast cell activation syndrome and mast cell activation syndrome introduced in Dec 2010 ( Akin et al 2010 ). This is being diagnosed by some Mastocytosis specialists and not others . the alternate diagnosis currently is Idiopathic - angiodeama =/_ urticaria +/_anphylaxis

 

Monoclonal mast cell activation – has extra mast cells in the bone marrow but not big enough to be defined as Mastocytosis. This is often tryptase negative . Bone marrow biopsy is required for diagnosis . It is felt that those with ididoapthic anaphylaxis may fall into this diagnosis .

 

Mast cell activation syndrome – has no extra mast cells , but the pts normal mast cells behave badly, triggering easily. All the medications , symptoms and triggers apply. This can be very complex to treat. Diagnostic criteria are being honed down . Currently testing is for urine histamine and prostaglandins in urine . ( Akin et al 2010 ).

 

Mast cell tryptase.

In most patients with systemic Mastocytosis , the serum tryptase concentration exceeds 20 ng/mL,  but a normal level of tryptase does not rule out either Mastocytosis or another mast cell activation disorder.

 

For mast cell activation conditions - Tryptase riase has been defined as between 2 samples -

First -taken on an averge day or 24 hours after all sysmptoms have resolved - is - value x 0.2 + 2(ng/ml)

 

Mast cell tryptase measures mast cell load not symptom severity . Bone marrow biopsies need to be done  with care and analysed at specialist centres to ensure accurate results . Because staining for mast cell tryptase  is complex . Sedation with benzodiazepines is used .

 

Mast cell activation can be autoimmune- notably due to hashimotos thyroiditis – seen more commonly in mast cell conditions   , adrenal, lupus or amiloyd . Due to other immunoglobulin’s – IGG, IGA.IGD - myasthenia gravis amongst others. There is also an autoimmunity to the persons own IGE

 

Autoimmune conditions , even if not mast cell activating directly act as a magnifier of any mast cell disease .

 

 

When a patient has an infection

 

Mast cells migrate , but don’t die so remain in those areas . Flares of cells can happen in any area of the body or several areas . An example is in Breast , a mass can show one day and be gone the next , this is where mast cells were active and have now settled . Any new symptoms should be reviewed by the relevant specialty .

 

Single system mast cell conditions

 

- Bladder, interstitial cystitis

Also known as neurogenic cyctitis . is due to mast cells, next to substance P neurons . The neuron fires and this causes the mast cell to degranulate- spill out contents in granules . The effect of the mast cell chemicals cause symptoms- pain ++, spasms , bleeding , stinging burning on passing urine with NO infection present

Treated with antihistamines . A drug which draws histamine out of the mast cell can be given but -MUST NOT BE in patients with Mast cell conditions because it destabilises Mast cells .

- Bowel mastocyctic enrocollitis

Is the preence of extra mast cells in the bowel. The contents of which causes local inflammation . This causes- pain, spasm , swelling of the bowel . Diarrhoea of liquid or mucous stools . Treated with Mast cell stabilisers for 6 weeks . Samples should be checked for ckit gene change .

 

 

Mast cells are known to be involved in the pathophysiology of migraines, (                         )  MS(                                    ), IBS - yellow link

Differential Diagnosis - Tests and working out what is going on

cutaneous masto

Mast cell Activation Disorders = Angiodeama and Urticaria

Download of diagnostic protocol ............................

 

Idiopathic Mast cell activation syndrome with anaphylaxis = Idiopathic anaphylaxis  

Mastocytosis compact Mast cell conditions causes MCAD - Diagnostic Proposal-1 Conditions list for idiopathic anaphylaxis differe http://www.youtube.com/watch?v=zaPo0r37wEc http://www.youtube.com/watch?v=w0ORhV9J5xU http://www.youtube.com/watch?v=ME979bUD1J8

Mast cell activation symptoms

http://www.labtestsonline.org.uk/understanding/analytes/catecholamine/tab/test http://www.carcinoid.org/ http://www.imperialendo.com/for-patients/endocrine-services/carcinoid-and-neuroendocrine-tumours http://cancerhelp.cancerresearchuk.org/type/carcinoid/about/symptoms-of-a-carcinoid-tumour http://www.imperialendo.com/for-doctors/endocrine-bible http://www.mayoclinic.com/health/carcinoid-syndrome/DS00690 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069946/?tool=pubmed

Link is 2011 - Most up to date complet review of differntail diagnosis and treatment -Afrin et al  @ free access article @

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874294/ http://www.hindawi.com/journals/grp/2012/950582/

Hyper IGE - More than allergy

 

A group of patients have very high IGE , not explained by the allergy test results . This is known as hyper IGE . It can be treated but many doctors are not aware of or have access to the best treatments . If IGE is over 100 ,then anaphylaxis is possible . If you or your patient has this please contact one of the speclists in the information under medical staff for treatment plans for you/ your patient

Idiopathic anaphylaxis - is anaphylaxis with no definable cause - be it allergy, trigger or autoimmune condition and is adiagnosis of exclusion .

 

30%of all presenting anaphylaxis is idiopathic.

 

The process by which the anaphylaxis occurs are as numerous as the number of triggers and trigger pathways . Within this there are some common themes in triggers -see opposite  

 

Patients with idioapthic anaphylaxis can have anaphylaxis daily or more or more infrequently. With lesser symptoms in between . Despite anaphylais orginally being described in , a consensus on what classifes anaphylaxis has been difficult to achieve .

 

The current guidelines (WAO 2011 0 deifine anaphylaxis as -

Eithor or both -

1) drop in blodd pressure causing presyncope -dizziness , glazing or loss of conciousness

 

2) breathing difficulties inc airway swelling , restricted lungs from muscle spasm , fluid or mucous (or all ) with or without stridor

 

Ring et al-described 4 stages of anaphylaxis and this is a useful way to look at anaphylaxis in relation to IA

 

For a full discussion of the causes of anaphylaxis and symptoms - click anaphylaxis link .

 

Also - The yellow link takes you to a full discussion on anaphylaxis on a website dedicated in info on Idiopathic Anaphylaxis

 

Idiopathic anaphylaxis

The most recant published paper on Idiopathic anaphylaxis -classifies IA -by symptoms ,frequency and severity .

 

Not all doctors use this criteria (greenburger 2006) but it can serve as useful guide to treatment needs and symptom severity .

 

With the publishing of the proposed diagnostic criteria for mast cell disorders .There is currently debate as to where patients with idiopathic anaphylaxis should be placed .this continues and for the time being the diagnosis idiopathic anaphylaxis should be used for patients with anaphylaxis with no known cuase .

 

All causes should be excluded inc HAE and autoimmune activation -causing anaphylaxis

 

the treatement follow the same guidelines for mast cell and mastocytosis . Some pts with IA respond well to immunomodulation , others xolair and others mast cell stabilisation .

 

The focus of care should be safety first Control of reactions -to reduce number to 1 per year as a goal and  avoidance as the 2 prongs of management

Complications of Mast cell conditions commonly seen  

Osteoprosis

Gastro osphegeal Reflux disease =/- gasritis

GORD ( GERD ) occurs when stomach acid leaks out of the stomach upwards into the oesphegus -were it causes burning.It can move up to the voal cords causing dmage or sit in the pharanx -leading to airway irritation and shortness of breath .

 

the pain from this is "typically" mid chest and not radiating .It can come on at any time .

-called heart burn ,reflux

Heart burn -should be investiagted as heart pain if there is any chance of heart issues  .

Pain which comes on with even moderate exercise should be treated as potential heart pain .

 

Heart pain can be - central chest , radiating to back, shoulders and left and right arm and jaw. In woman heart pain presents differently often as back pain and shortness of breath,daibetics may not feel chest pain due to nerve damage and any signs -shortness of breath, shoulder pain or looking pale, grey or sweaty should be investiagted .

 

So- now we know its heart burn - why ?

reflux happens associated with-

1) larger people

2) hiatus hernia

3) high acid level .

 

In mast cell the stomach acid level is very high .This is for several reasons

 

Acid production is stimulated by histmine -which we know is amast cell chemical .

 

Histamine - is produced in Gcell -gastrin producing cells - It is released by G cells in the antrum of the stomach, duodenum, and the pancreas. It does this by taking in histidine (from dietry protien) and histidine carboxilase working - This histamine activates these cells to produce gastrin .

 

Histamine also stimulated d cells to produce somastatin - This should inhibit the process -BUT- somastatin is amast cellactivator so in mast cell disease the means further mast cell activation .

For several decades osteoprosis has been a known complication of Mastocytosis and Ididopathic Anapahylaxis ,angiodeama and urticaria .

 

So is this due to bone modeling or remodeling ?

 

In recant times the reasons for this have been revealed.

 

Several mast cellchemicals have a role in bone metabolism .

 

Histamine -receptor 3

 

 

Serotonin

 

 

Il1

 

 

Il6

acid secretion 495px-Control-of-stomach-acid-sec

Gastrin then stimulates the entrocromaffin clike cells to produce more histamine

 

Gastrin also stimulates preital cells -acid producing cells .histamine also stimaulates acid producing cells .This produces a physical high gastrin level , high histamine and high acid .

 

Gastrin stimulates parietal cell maturation and fundal growth.

Causes chief cells to secrete pepsinogen, the zymogen (inactive) form of the digestive enzyme pepsin.

Increases antral muscle mobility and promotes stomach contractions.-so excess= more contractions

Strengthens antral contractions against the pylorus, and relaxes the pyloric sphincter, which stimulates gastric emptying.

Plays a role in the relaxation of the ileocecal valve.

Induces pancreatic secretions and gallbladder emptying.

 

Gastrin also impacts lower (o)esophageal sphincter (LES) tone, causing it to relax. ( Gregory et al 1969) Taking this into consideration, high levels of gastrin may play a role in the development of some of the more common LES disorders such as acid reflux disease.

 

High gastrin would bring an expection of zollinger -         syndrome -were the is an over proliferation of entrocromaffin like cells .This can be a gastroma (stomach carciniod ) .So a biopsy of these cells on endoscopy ( oespogeal, gestric, dueodenal camera down ) to confirm this as a diagnosis .

 

But in mast cell ahigh gastrin can be expected without over proliferation of entrocromaffin like cells .

 

Excess acid produces inflammation of the stamch lining known as gastritis - many mast cell patients expereince this -many describe it as -their stomach trying to digest glass .

 

With somastatin and stress - CRH activating mast cells - The stimulation leads to constant histamine release -which further increses acid level .

Other mast cell chemicals - go on to further activate mast cells and interleukins -il4 ,IL5 and TNFalpha also continue to perpetuate the infammation.

Bone metabolism

 

Bone is 90% collagen . There are 3 types of cells which control the lay down of calcium and potassium into the collagen to make the bone -

 

Osteoblasts synthesize the bone matrix and are responsible for its mineralization. They are derived from osteoprogenitor cells, a mesenchymal stem cell line.

 

Osteocytes are inactive osteoblasts that have become trapped within the bone they have formed.

 

Osteoclasts break down bone matrix through phagocytosis. Predictably, they are derived from the monocyte (macrophage) cell line. Think of osteoclasts as the "bone version" of the macrophage. Their activity occurs along their ruffled border, and the space between the osteoclast and the bone is known as Howship's lacuna.

 

In adults when they have stopped growing the process of bone building or degeration takes 90 days .

 

Bone structure

 

From the outside in

stomach

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http://medcell.med.yale.edu/histology/bone.php BoneCompact-and-spongy

Osteoprogenitors - pre osteoblasts are induced to differentiate under the influence of growth factors, in particular the bone morphogenetic proteins (BMPs).

 

Aside from BMPs, other growth factors including fibroblast growth factor (FGF),

platelet-derived growth factor (PDGF), t

ransforming growth factor beta (TGF-β) may promote the division of osteoprogenitors and potentially increase osteogenesis

 

 

 

http://www.search.com/reference/Osteoblast

 

The balance between osteoblast and osteoclast activity governs bone turnover and ensures that bone is neither overproduced nor overdegraded. These cells build up and break down bone matrix, which is composed of:

 

Osteoid, which is the unmineralized matrix composed of type I collagen and glycosaminoglycans (GAGs).

Calcium hydroxyapatite, a calcium salt crystal that gives bone its strength and rigidity.

 

Bone is divided into two types that are different structurally and functionally. Most bones of the body consist of both types of bone tissue:

Compact bone, or cortical bone, mainly serves a mechanical function. This is the area of bone to which ligaments and tendons attach. It is thick and dense.

 

Trabecular bone, also known as cancellous bone or spongy bone, mainly serves a metabolic function. This type of bone is located between layers of compact bone and is thin and porous. Located within the trabeculae is the bone marrow.

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Ring-

 

Desceibes stages of anaphylaxis

Stage 1

 

 

Satge2

 

 

 

Stage3

 

 

 

Stage4

So Rings stages are 4 in number . many patients are shocked to find their daily symptoms are level 2 .

 

As such anaphylaxis can be graded .mild, moderete ,life threatening and RIP .It is important to remeber that anaphylaxis is un predictable and to follow your instanict regards to when to seek treatment .

Patients with idiopathic anaphylaxis cna move through the stages quickly or ata slower pace .

Counselling must be given not only on epipen technique but also when  to use the pen -which should be when the patient knows they need it . As waiting can be fatal (WHO2012)

Angiodeama http://emedicine.medscape.com/article/135208-overview

Mast cell conditions can be seen as on a line of severity from minor allergy at one end and Aggressive systemic mastocytosis at the other .

 

Some see Mast cell as one condition but research doesnt back this up .So on this page each condition is discussed individually .

 

Individuals can have 2 conditions - Say systemic mastocytosis and minor allergies - in line with the general population level of 20% but one can exist without the other

 

Anaphylaxis cna feature in several of these conditions and this is discussed in each section .

 

Mast cell activation syndrome is a newer diagnosis for Idiopathic uritcaria and/or angiodeama .idiopathic anaphylaxis is a seperate condition .But the individual may also have chronic angiodeama. uriticaria or idiopathic angiodeam and urticaria .

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Minor Allergy

The Atopic March

Skin Only (cutanious ) Mastocytosis

Asthma

Atopic dermatitis /excema

Rhinitis

 

 

IBS ( certain classes

Migraines

Painful Bladder Syndrome /Interstitial cystitis

Mastocyctic Entrocollitis

 

Multiple Allergies

Systemic Mastocytosis -Indolent and Smouldering

A

N

A

P

H

Y

L

A

X

I

S

Mast cell  Activation Syndrome

Idiopathic

 

Anaphylaxis

Uritcaria  

and Angiodeama

Cause Known  ...

minor Conditions

Cause Unknown -idiopathic -Angiodeama and / or urticaria

ANAPHYLAXIS

Idiopathic Mast Cell Activation Syndrome with anaphylaxis

 

Major Conditions

Monoclonal

Mast cell activation syndrome

Agressive Systemic mastocytosis

3% of all pts

Visual reprensatation of mast cell conditions from minor at top to major at the bottom

Single System mast cell conditions..

Link button
mast cell definitions

2012 - The mast cell activation conditions (MCA's ) were further defined as

1) Primary

# Systemic mastocytosis

# Monoclonal mast cell activation syndrome

 

2) Secondery

# IGE allergy

# Parasite /bacteria infection

# Autoimmune conditions

 

3) Idiopathic

Excluded all other likley conditions . See testing

Anaphylaxis http://www.iainfoctr.com/anaphylaxis.php

Symptoms will vary on several factors

1) underlying conditions ~ autoimmunes being active will increase symptoms.

 

2) Triggers experienced ~ some cause activation alone .Others need the individual to be more sensitive .E.g hormones in ladies ~ oestrogen leads to leuoctrine release and airway symptoms.

 

3) Time since last reaction ~ several mast cellchemicals cause further mast cellactivation making another reaction more likley automatically internally or increasing sensitivity to triggers

For MCAS and Idiopathic Anaphylaxis

Link button

Angiodeama - is seen 50% of the time with uricaria -I will discuss this seperately

 

Angiodeama is deep swelling in the skin and other organs. It is either -

1) Histamine based - True allergy . Systsemic mastocytosis and mast cellactivation syndromes

 

2) Kinin -heriditory angiodeama

 

3) Autoimmune conditions -commonly hashimotos thyriodditis 12-18% of patients with angiodeama have tyroid antibodies .