Find Your POTS Cause: The Wide World of Mast Cells (Sourced)

The proposed relationship between POTS and MCAD.

MCAD and Mastocytosis are a confusing set of diseases and conditions.  What aren't  these days?   I'd like to post about a nice, simple, straight forward and easy to understand condition for once, but alas, MCAD is exactly the opposite.


 What are Mast Cells?

Mast cells are cells of the immune system that are found around blood vessels in the skin, gastrointestinal tract, respiratory tract, and genitourinary tract, and are highly associated with nerves. They release chemicals including histamine that are very irritating and cause itching, swelling, and fluid leakage from cells.

"Mast cells are known to be the primary responders in allergic reactions, orchestrating strong responses to minute amounts of allergens. Several recent observations indicate that they may also have a key role in coordinating the early phases of autoimmune diseases, particularly those involving auto-antibodies."

What is MCAD?
As desribed technically, "Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells' mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation."

What does that mean?  In simpler terms - MCAD is a collection of hard to diagnose (because they often don't show up in standard blood work) conditions related to "mast cells behaving badly."  Mast cells are almost everywhere in the body.  When they break down, it is called degranulation, and in MCAD the mast cells do this in a seemingly random way; releasing histamine that the body reacts to, causing all kinds of skin reactions, anaphylaxis (throat closing/itching/blood pressure drops, etc...), and even causing heart rate fluctuations and shortness of breath in some.

MCAD is also called MCA, or MCAS (the "S" stands for syndrome), and the current definitions by the WHO (World Health Organization) are being debated.  Currently because of the WHO definitions of MCAD, it is very hard to get a solid diagnosis, and it is an under-diagnosed and misunderstood condition by many physicians. 



What is the difference between MCAD and MASTOCYTOCIS:

Mastocytosis is classified into multiple categories, but the basic definition is that there are too many mast cells present in the body - whether it be a localized area (like the skin or an organ) or the entire body.   This is different from MCAD in that there are normal levels (at least in blood tests such as serum tryptase) of mast cells, they just degranulate at the wrong time (or "misbehave" inappropriately) with MCAD.

"Mastocytosis should be suspected in patients who present with a constellation of symptoms, including flushing, abdominal pain, diarrhea, unexplained syncope, and classic urticaria pigmentosa lesions. Diagnosis should be established by a bone marrow biopsy in all adults. Staging should be performed to assess disease burden and evidence of end-stage organ damage. Patients should be offered symptom-based treatment and cytoreductive therapy only for aggressive systemic mastocytosis or an associated hematologic malignant neoplasm."

Diagnosis and Criteria:

(from the Mastocytosis Society, a re-post of the WHO definition of types of Mastocytosis only , they have yet to accept or define MCAD)


Diagnosis and Classification

CM is diagnosed by the presence of typical skin lesions and a positive skin biopsy demonstrating characteristic clusters of mast cells. The preferred method of diagnosing is via bone marrow biopsy. The World Health Organization (WHO) has established criteria for diagnosing SM, restated below:

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

Minor Criterion:
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 non-mast cell associated hematological 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:
Urticaria pigmentosa (UP) --- also known as maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma.

Indolent Systemic Mastocytosis:
These patients fit the criteria for systemic mastocytosis and may have an enlarged liver or spleen. The GI tract may also be affected. The majority of adult patients fit into this category. Mediator-related symptoms are common, but the grade of bone marrow infiltration is low, usually less than 5 percent. Mast cells usually co-express CD2 and CD25 with KIT and contain the KIT mutation D816V. In most patients 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. Treatment usually includes mediator-targeting drugs, including antihistamines, but does not usually require cytoreductive agents, except for considering IFN-2b for severe osteoporosis.

Isolated Bone Marrow Mastocytosis (BMM) and Smouldering Systemic Mastocytosis (SSM) are subvariants of indolent SM. BMM is characterized by absence of skin lesions, lack of multiorgan involvement, and low or normal serum tryptase level. BMM patients may or may not require treatment for mediator-related symptoms. In SSM two or three of the following, which indicate high burden of mast cells may be observed:

1. Infiltration grade is greater than 30 percent in bone marrow and total tryptase levels greater than 200ng/mL.
2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria for an MDS or MPD.
3. Organomegaly: Palpable hepatomegaly, splenomegaly, or lymphadenopathy (on CT or ultrasound) greater than 2 cm without impaired organ function.

Systemic Mastocytosis with Associated Clonal Hematologic Non-Mast Cell Lineage Disease (AHNMD)
These patients for the criteria for systemic mastocytosis and they fit the WHO creiteria for myelodysplastic syndrome, myeloproliferative syndrome, acute myeloid leukemia, or non-Hodgkin’s lymphoma. These patients often do not have urticaria pigmentosa-like skin lesions. Successful treatment of the hematologic disorder has not been shown to change or improve their systemic mastocytosis.

Agressive Systemic Mastocytosis:
In this rare subvariant, these patients fit the criteria for systemic mastocytosis; and their bone marrow biopsy reveals abnormal blood cell formation that does not fit the WHO criteria for AHNMD as listed above. These patients are characterized by bone marrow aspirate smears showing less that 20% of the cells to be mast cells, no mast cells identified in the circulating blood, and the presence of at least one finding below:
1. An abnormal blood count;
2. An enlarged liver, and liver function is impaired;
3. An enlarged spleen, and its function is abnormal;
4. Malabsorption with weight loss is present and is due to mast cell infiltration in the GI tract that interferes with its normal function;
5. Bone involvement is seen with large areas of calcium loss and/or pathologic fractures; or
6. Other internal organs are affected by mast cell infiltrates with impairment of organ function.

Mast Cell Leukemia:
In this rare subvariant, these people fit the criteria for systemic mastocytosis, and a bone marrow aspirate smear shows that 20% or more of the cells are mast cells of 10% or more mast cells are seen in circulating blood. The shape of mast cells and their nuclei have malignant features.

Mast Cell Sarcoma:
Mast cell sarcoma is an extremely rare tumor. In three cases reported so far, the tumor has been located in the larynx, in the colon, and inside the skull. Prognosis is very poor. People with mast cell sarcoma have a single tumor made up of abnormal mast cells. They do not fit the criteria for systemic mastocytosis, they have no skin lesions, and pathological examination of the tumor shows it to be highly malignant with an aggressive growth pattern.

Extracutaneous Mastocytoma:
This is a very rare finding. Patients with extracutaneous mastocytoma do not fit the criteria for systemic mastocytosis, they have no skin lesions, and pathological examination of the lesion shows it to be made up of normal or nearly normal appearing mast cells with a non-aggressive growth pattern.

When aggressive disease or an associated hematological disorder is suspected, further evaluation of the patient may include:
1. X-ray or CT scan of the chest, looking for evidence of significantly enlarged lymph nodes (greater than 2 cm in diameter);
2. X-ray of the skeletal system, looking for osteoporosis, osteosclerosis, or areas where calcium has been completely lost from bone;
3. CT scan or ultrasound of the abdomen, looking for enlarged liver or spleen, enlarged lymph nodes, or the collection of fluid; and
4. Endoscopy and biopsy of the GI tract, looking for evidence of mast cell infiltration, ulcers, or areas of bleeding.

Other tests may be done, as indicated, if there is a suspected hematologic disorder or evaluate the individual patient’s symptoms. By contrast, further testing should be kept to a minimum when the disease seems to be confined to the skin, and in most pediatric cases.

From NATURE: Mast Cells as amplifiers of autoimmune response

THE NEWLY PROPOSED CRITERIA for MCAS:
(from Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. )

Criteria proposed to define mast cell activation disease (for references, see text).

Criteria to define mast cell activation syndrome	WHO criteria to define systemic mastocytosis
Major criteria	Major criterion
1. Multifocal or disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (e.g., gastrointestinal tract biopsies; CD117-, tryptase- and CD25-stained)	Multifocal dense infiltrates of mast cells (>15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (CD117-, tryptase- and CD25-stained)
2. Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release syndrome)
Minor criteria	Minor criteria
1. Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies	1. Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
2. Mast cells in bone marrow express CD2 and/or CD25	2. Mast cells in bone marrow express CD2 and/or CD25
3. Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved.	3. c-kit mutation in tyrosine kinase at codon 816 in mast cells in extracutaneous organ(s)
4. Evidence of a pathologically increased release of mast cell mediators by determination of the content of	4. Serum total tryptase >20 ng/ml (does not apply in patients who have associated hematologic non-mast-cell lineage disease)
• tryptase in blood
• N-methylhistamine in urine
• heparin in blood
• chromogranin A in blood
• other mast cell-specific mediators (e.g., leukotrienes, prostaglandin D2)

The diagnosis mast cell activation syndrome is made if both major criteria or the second criterion and at least one minor criterion are fulfilled. According to the WHO criteria [1], the diagnosis systemic mastocytosis is established if the major criterion and at least one minor criterion or at least three minor criteria are fulfilled.

Frequent signs and clinical symptoms ascribed to episodic unregulated release of mast cell mediators (modified from [12]; further references therein; an exhaustive survey is given in [50]).

HOW DOES THIS RELATE TO POTS?

There seems to be a strong correlation between the HyperPOTS (elevated catecholemines in the blood) population and MCAD.  Also, many POTSies present with flushing, and this can possibly be caused by MCAD (but also can be caused by autoimmune issues and dopamine).

Anaphylaxis can be triggered by standing up and also by exercising.   This can be triggered by the blood vessels dilating (opening up) in response to mast cells going bonkers and releasing histamine.  If the increased heart rate does its job and gets the blood pumping to the brain and other organs, you may not see a drop in blood pressure, just an increase in heart rate.  Either way, if you have POTS, and flushing, and especially random reactions (skin and/or anaphylaxis) to food, chemicals, and other allergens, it may be worth checking out.  

Here is the technical theory published by the researchers at Vanderbilt:

"Mast cells are localized in close proximity to blood vessels and peripheral nerves and are therefore strategically positioned to modulate sympathetic activity, vascular tone, and angiogenesis.²⁰ Histamine is a powerful vasodilator that could explain the cutaneous vasodilatation responsible for flushing. With regard to the pathophysiology underlying the association between POTS and MCA, we propose a positive feedback loop by which MCA, with the subsequent release of vasoactive mediators, may contribute to vasodilation, reflex sympathetic activation, central volume contraction, norepinephrine release, and orthostatic intolerance (Figure 4). Conversely, our results indicate that exercise can lead to MCA, presumably through sympathetic activation."

MCAD has also been closely linked to EDS, JHS, and autoimmune diseases (to complicate things further).  It seems these weird conditions come in clusters - lucky for us!  

SIGNS AND SYMPTONS OF MCAD

Abdominal	abdominal pain, intestinal cramping and bloating, diarrhea and/or obstipation, nausea, non-cardiac chest pain, Helicobacter pylori-negative gastritis, malabsorption
Oropharyngeal	burning pain, aphthae
Respiratory	cough, asthma-like symptoms, dyspnea, rhinitis, sinusitis
Ophthalmologic	conjunctivitis, difficulty in focusing
Hepatic	splenomegaly, hyperbilirubinemia, elevation of liver transaminases, hypercholesterolemia
Splenomegaly
Lymphadenopathy
Cardiovascular	tachycardia, blood pressure irregularity (hypotension and/or hypertension), syncope, hot flush
Neuropsychiatric	headache, neuropathic pain, polyneuropathy, decreased attention span, difficulty in concentration, forgetfulness, anxiety, sleeplessness, organic brain syndrome, vertigo, lightheadedness, tinnitus
Cutaneous	urticaria pigmentosa, hives, efflorescences with/without pruritus, telangiectasia, flushing, angioedema
Abnormal bleeding
Musculoskeletal	muscle pain, osteoporosis/osteopenia, bone pain, migratory arthritis
Interstitial cystitis
Constitutional	fatigue, asthenia, fever, environmental sensitivities

Sources and Links (the most recent and updated I could find):

• Dr. Afrin's Presentation to the Mastocytosis Society (shown in slide form instead of text): I narrowed down slides of interest (with criterea and info) if you don't want to read all 150!  Slides: 7, 8*, 44, 47-51, 54-57, 79, 83, 84, 90, 91*-94, 98*-100, 115 - 119, 127-128, dx criteria 129-134, treatment 135-142, then keep reading for a spontaneous human combustion case!  

• Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options.  Gerhard J Molderings, Stefan Brettner, Jürgen Homann, and Lawrence B Afrin, J Hematol Oncol. 2011; 4: 10. Published online 2011 March 22.***This is the best article I have found and HIGHLY suggest you print it and show it to your doctor if you suspect you have MCAD.

•  Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders. Cyndya Shibao, Carmen Arzubiaga, L. Jackson Roberts II, Satish Raj, Bonnie Black, Paul Harris, Italo Biaggioni. Hypertension. 2005; 45: 385-390.

•  Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, Castells M, Escribano L, Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Sperr WR, Triggiani M, Valenta R, Horny HP, Metcalfe DD. Int Arch Allergy Immunol. 2012;157(3):215-25. Epub 2011 Oct 27.

• Mast cells. Metcalfe DD, Baram D, Mekori YA. Physiol Rev. 1997 Oct;77(4):1033-79.

   
•  Butterfield JH. Systemic mastocytosis: clinical manifestations and differential diagnosis. Immunol Allergy Clin N Am 2006 Aug; 26(3): 487-513. 

• Bains SN, Hsieh FH. Current approaches to the diagnosis and treatment of systemic mastocytosis. Ann Allergy Asthma Immunol. 2010 Jan;104(1):1-10; quiz 10-2, 41.

• Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience.  Dr. Grubb, 2011 ***Full text - great guide.

 Support Organizations/Info:

• Mast Cell Disorders Forum
• The Mastocytosis Society
• List of Physicians specializing in MCAD (from the Mastocytosis Society) 
• The UK Mastocytosis Group