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Get okay

Last week was hard for me.  I’m not entirely sure why it was so hard.  I got bad news, but frankly, I get bad news a lot.  Sometimes it’s harder for me, and I can’t always predict when those times will be.  It’s one of the weird aspects of chronic illness. 

I had a couple days of feeling sorry for myself, which I also need to do occasionally.  Sometimes I need to sleep a lot and complain and wallow in my unfortunateness for a bit.  This invariably leads to getting mad, and that’s just not a place I like to be.  I find that it’s okay to be mad about being sick in an abstract, transient way, but not as a state of being.  I’m not really a person who is angry about being sick, and I think I’m much happier for that fact.
Friday night, I came home from work and was exhausted.  I have been getting really into these MCAS/MMAS papers (which is great – I have learned so much and I’m super excited to share) and I have had a lot of work stuff happening and my brain was fried.  I decided it was time for some self care to head off a mast cell spiral from stress. I put out the (reverse?) bat signal that I wouldn’t be around for the weekend.
I had picked up a bunch of protein drinks and baby food purees to try, so I organized them and tried out a few.  I made some vegetable stock, baked some Red Kori and Carnival squashes and made a sweet Red Kori/ apple soup and a savory Carnival/ caramelized onion soup with a little grated cheese.  I heated up some cranberries and raspberries with sugar and lemon zest and mixed them with milk and yogurt for breakfast drinks.  I did all the dishes while I cooked, tasted everything and sang along to Ingrid Michaelson.  I finished the night with 10 mason jars full of no solids meals for the week.
I woke up Saturday morning to the smell of rain and the chill of autumn blowing into my bedroom.  Me and Story snuggled under my heated blanket and watched American Horror Story for a while.  I cleaned out my closet and cabinets and threw away/ set aside to donate lots of things.  I walked the dogs, did some writing and ate a lot of very buttery, very salty mashed potatoes. 
Today, I woke up really tired and sore, but for the first time in a very long time, I wasn’t nauseous.  I am still very swollen and my GI tract feels like it’s burning, but I am bleeding less.  I’m not enjoying this no solids diet but I have to say that it is helping.  I did some yoga and took Story for a long walk.  I hung out with the family and watched a movie and tried to just relax.
I’m feeling a lot more like myself.  I’d really rather not need biopsies and scopes and surgery, but you get what you get, and it’s easier to just get it over with.  In response to a post last week about how I had gotten bad news, a friend of mine told me to, “Get a plan – and get okay with it.”  It’s great advice and a motto for living with masto if ever I have heard one. 
So I have a plan.  And I’m okay with it.

Mast cells and cardiac and vascular dysfunction

Mast cells have been implicated in several types of cardiac and vascular dysfunction.  Mast cells are thought to contribute to rupture of atherosclerotic plaques by mediator release.  They are found around blood clots in the body.  Mast cells may destabilize them and mature them by releasing heparin and degrading fibrinogen with tryptase. Increased numbers of mast cells are associated with coronary vasospasm. 
Mast cell mediator levels are often higher in vascular and cardiac events.  In patients who die from coronary heart disease, the histamine concentration in the coronary artery than in control subjects.  Higher white blood cell, platelet and plasma histamine levels are found in patients with peripheral vascular disease. Increased histamine levels are found in patients with both stable coronary artery disease and acute coronary syndrome.  Plasma histamine is elevated in the great cardiac vein of 8/11 patients with variant angina. 
One study found that tryptase is higher in patients without acute coronary syndrome undergoing catheterization, compared to patients with and without obstructive coronary disease.  In this study, patients in the highest 25% of tryptase values had 4.3x greater risk for coronary artery disease.  Tryptase is being investigated as a marker to identify asymptomatic patients with coronary artery disease and to track efficacy of treatment. 
Mast cell mediators are also elevated in non-allergic coronary events, indicating that there is a common pathway for both allergic (Kounis syndrome) and non-allergic cardiac episodes.  Two cholesterol lowering medications, cervistatin and atorvastatin, inhibit stem cell factor (SCF) mediated differentiation of mast cells.  Lovastatin inhibited IgE-mediated degranulation.

References:
Ribatti D, Crivellato E. Mast cells, angiogenesis, and tumour growth. Biochim. Biophys. Acta Mol. Basis Dis. 2012 Jan; 1822(1):2-8.
Glowacki J, Mulliken JB. Mast cells in hemangioma and vascular malformations. Pediatrics 1982; 70(1):48-51.
Kolck UW, Alfter K, Homann J, von Kügelgen I, Molderings GJ. Cardiac mast cells: implications for heart failure. JACC 2007 Mar 13; 49(10):1106-1108.
Biteker M.  Current understanding of Kounis Syndrome.  Expert Rev Clin Immunol 2010 Sep;6(5):777-88.

No solids, clear liquids and NPO

I got phone calls from three of my doctors today.  None of them realized the other two also called.  It was a little funny.
One of the doctors told me they were scheduling an endoscopy and a colonoscopy to get a really thorough look at my GI tract.  They will take biopsies from various parts and stain them to see if my mast cells are generally being terrible people (my money is on this) or if it is something else (I’m looking at you, eosinophils.)  So there’s that.
Another one of my doctors said that in light of the swelling and my persistent bleeding, that I should stop eating solid foods and go on a liquid diet as a stop gap measure to try and stem the inflammation.  I was not expecting to hear this today and I’m feeling pretty sorry for myself, which is not really my style, but is my right.
It got me thinking about the fact that I am pretty used to not eating at all (NPO), or to not eating solids, or to only consuming clear liquids.  This is a side effect of being the vessel for a GI tract that feels it is my mortal enemy.  Before my colostomy surgery, I didn’t eat anything but clear liquids for a few days, while at the same time taking impressive measures to clean the surgical area.  And then I didn’t eat anything for several days after due to post-operative ileus (intestines not moving.) 
So here are my tips for not eating solids or not eating anything but clear liquids.
Figure out which meds will make you hungry.  I take high doses of antihistamines and daily steroids.  These medications increase appetite.  Steroids are actually used in elderly patients to stimulate appetite to keep up their energy.  When I have to take my large doses of antihistamines and steroids, I drink at least 240ml of pureed food (squash soup is a mainstay in my house) or drink at least 500ml of clear liquid about thirty minutes before I take them.  If you are on an NPO (nothing by mouth) order, I recommend starting bolus fluids about thirty minutes before you take your meds.
Set a schedule for liquids and keep it.  Even if you third space like me and oral fluids won’t go to where they’re needed, they will make you feel fuller and suppress appetite.  Keep in mind that suddenly consuming huge amounts of water when you don’t usually will skew your electrolytes, so be sure that you alternate with electrolyte solution.  This is especially true if you have POTS.
Learn how your current dosing affects you without food.  Medication is more available to your body the less solid food you are ingesting.  The cultural touchstone most of us are familiar with is drinking alcohol on any empty stomach.  If you drink on an empty stomach, you get drunker much faster because the alcohol is more available. Medication is the same way.  If you eating thick liquids (pureed food, smoothies), the meds will be more available than if you are eating solid food.  If you are drinking clear liquids, the meds will be more available than if you are eating pureed food.  The difference in both efficacy and side effects can be dramatic.  I recommend having someone with you for the first 48 hours or so until you can predict your reaction to meds. 
Get something for nausea.  Sometimes when you just stop eating, your body misinterprets the problem as there not being enough stomach acid, so it makes extra.  This causes “sour belly” and makes you nauseous.  Additionally, long term hunger will make you nauseous generally, so getting a script for Zofran is helpful. 
It’s okay to add flavor.  When I can only do clear liquids, I make flavor rich, brothy soups and then strain all the solids out.  This way it tastes like chicken soup and not like broth, which really turns my stomach.  Some people chew herbs and spit them out before drinking fluids so that it tastes better.
You are going to be more tired than usual until your body acclimates.  Plan for it. 

So when I am on no solid foods, my day generally looks like this:
630am: Wake up, drink coffee and take thyroid med on empty stomach.
700am: Drink morning milkshake of whatever I feel like milkshaking.  Bemoan the lack of solids in the milkshake.
730am: Take morning meds, including antihistamines and steroids.
800am: 500ml of water.
900am: Cromolyn, 500ml of water.
1000am: Smoothie/soup/whatever.
1100am: 500ml of electrolyte solution.
1200n: Cromolyn, 500ml of water, antihistamines.
1230p: Smoothie/soup/whatever.
200p: 500 ml of electrolyte solution.
300p: Cromolyn, 500ml of water, antihistamines, steroids.
530p: 500ml of water.
600p: Smoothie/soup/whatever.
700p: Cromolyn, 500ml of water.
1000p: Hook up overnight IV fluids (2L.)

1030p: Night time meds. 

This is very generic and gets moved around because I often nap in the afternoon.  I generally drink about 4L of water/electrolyte fluids a day when not eating solids and about 3L a day when I am eating solids. Not eating sucks, but being hungry all the time and not being able to eat sucks worse.  This makes the hunger bearable. 

Mast cell mediators: Recommended testing for MCAS diagnosis

Lab tests specific to mast cell activation for suspected MCAS patients should include serum tryptase, serum chromogranin A, plasma histamine, chilled plasma PGD2, stat chilled plasma heparin, chilled urine for PGD2, PGF2a and n-methylhistamine. 
Tryptase is the most famous mast cell mediator.  It is a complex molecule with many functions in the body.  It is easily damaged by heat and has a short half-life in the body (6-8 minutes in health subjects, 1.5-2.3 hours in patients with hypersensitivity reactions.  In separated serum, it can last approximately four days.  Serum tryptase value is usually normal in MCAS patients, but sometimes it is elevated.  Tryptase values that show an increase of 20% + 2 ng/ml above the baseline level are considered diagnostic for MCAS.
Chromogranin A is a heat-stable mast cell mediator.  High levels can suggest MCAS, but other sources must first be ruled out, such as heart failure, renal insufficiency, neuroendocrine tumors and proton pump inhibitor (PPI) use.  Starting or stopping PPI therapy will generally cause a change in value within five days.  Once other causes have been excluded, serum chromogranin A can be considered a reliable marker of mast cell activity. 
Heparin is a very sensitive and specific marker of mast cell activation.  However, due to its quick metabolism in the body, it is very difficult to measure reliably.  It has a very short half life and quickly deteriorates, even when refrigerated.  Values above 0.02 anti-Factor Xa units/ml are abnormal, but many commercial tests cannot test that low.  Elevated plasma heparin is sometimes found in MCAS patients. 
Histamine is also released by basophils, but the majority is released by mast cells.  It is heat stable and has a short half life in the body.  Serum histamine peaks at about 5 minutes after release and returns to baseline within 15-30 minutes in most patients.  In separated plasma, it is stable at room temperature for at least 48 hours.  It is broken down to n-methylhistamine, which is more stable and can be measured accurately longer.  N-methylhistamine is usually measured in a 24 hour urine test to account for the variability in release over the course of the day. 
Prostaglandin D2 is produced by several other cell types, but mast cell release is responsible for the dominant amount found in the body.  MCAS patients typically produce much higher levels of PGD2 than n-methylhistamine.  PGD2 is less stable than histamine, being metabolized completely in an estimated 30 minutes.  Its metabolite, PGF2a, is the preferred compound for detection due to its superior stability.    Accurate prostaglandin testing relies upon refrigeration of the sample from the start of collection through testing.  NSAIDs inhibit prostaglandin production and can lower PGD2 in blood and urine.  Renal insufficiency may produce an inaccurately low test value, but elevated prostaglandins are sometime seen in patients with renal disease.  Prostaglandins D2 and F2a can be tested in serum, but 24 hour urine samples are considered more accurate.

Leukotriene B4 and cysteinyl leukotrienes C4, D4 and E4 have been noted to be elevated in SM patients and during acute asthma attacks.  Though commercial testing for these compounds is not easily accessible, but they may be elevated in MCAS patients as well.  Other less specific mast cell mediators that are sometimes abnormal in MCAS patients include Factor VIII, plasma free norepinephrine, tumor necrosis factor alpha, and interleukin-6.

References:
Sur R, Cavender D, Malaviya R. Different approaches to study mast cell functions.  Int. Immunopharmacol. 2007 May;7(5):555-567.
Pregun I, Herszényi L, Juhász M, Miheller P, Hritz I, Patócs A, Rácz K, Tulassay Z. Effect of proton-pump inhibitor therapy on serum chromogranin A level. Digestion 2011; 84:22-28.
Seidel H, Molderings GJ, Oldenburg J, Meis K, Kolck UW, Homann J, Hertfelder HJ. Bleeding diathesis in patients with mast cell activation disease. Thromb. Haemost. 2011 Nov; 106(5):987-989.
Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H. Biochemical markers of anaphylactoid reactions to drugs: comparison of plasma histamine and tryptase. Anesthesiol. 1991 Dec; 75(6):945-949.

Takeda J, Ueda E, Takahashi J, Fukushima K. Plasma N-methylhistamine concentration as an indicator of histamine release by intravenous d-tubocurarine in humans: preliminary study in five patients by radioimmunoassay kits. Anesth. Analg. 1995; 80:1015-1017.

Maclouf J, Corvazier E, Wang ZY. Development of a radioimmunoassay for prostaglandin D2 using an antiserum against 11-methoxime prostaglandin D2. Prostaglandins 1986 Jan; 31(1):123-132.
Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton LA, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK. Catecholamines in murine bone marrowderived mast cells. J. Neuroimmunol. 2001 Oct;119(2):231-238.
Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin. Nature 1990 Jul 19; 346:274-276.

Cardiovascular symptoms of MCAS

MCAS patients often have a number of cardiovascular symptoms.  In true mast cell disease fashion, these symptoms often represent both ends of the spectrum.
Heart palpitations are the most common cardiac complaint, with true rhythmic abnormalities being fairly rare.  Tachycardia is also very common, but occasionally slow heart rate (bradycardia) is reported.  In bradycardic patients, no obvious cause for this can be identified.  Both low and high blood pressure can be seen, many times in the same patient, sometimes even following one after the other in a short period of time.  These changes in blood pressure often have no clear trigger.
True syncope (fainting) is uncommon in MCAS, but presyncope (lightheadedness, weakness, dizziness or vertigo) affects the majority of patients.  These presyncope episodes can be distinct from POTS symptoms, and may not be related to position.  Some patients experience as many as several episodes a day.  When tested for POTS with tilt table, MCAS patients may or may not be positive.  However, when treated for POTS, mast cell patients in general only see mild reduction in their presyncope episodes, with little improvement in their other symptoms.
MCAS patients often complain of chest pain, which may or may not reveal ECG abnormalities.  This type of pain is generally localized specifically to the chest and does not radiate down the arm.  Chest pain must be carefully evaluated due to the potential for two rare cardiac syndromes.  Additionally, mast cell disease can indirectly cause congestive heart failure by the long term action of histamine. 
Takotsubo syndrome, or stress-induced cardiomyopathy, is caused by sudden weakening of the myocardium that causes ballooning of the left ventricle.  It can cause acute heart failure, ventricular arrhythmias, and acute heart failure.  Angiography shows that there is no coronary artery defect to explain the left ventricular abnormalities.  If the patient survives, the left ventricle typically returns to normal after about eight weeks.  This does not occur as a result of an allergic reaction, but is sometimes seen in patients with idiopathic anaphylaxis.  In 75% of patients, serum catecholamines are elevated, a finding sometimes seen in MCAS patients.  Due to severe emotional stress frequently being the trigger for the cardiac event, Takotsubo syndrome is also known as broken heart syndrome.
Kounis syndrome is also known as allergic angina or allergic myocardial infarction.  In these patients, there are no obstructive lesions in the coronary artery.  Patients suffer severe chest pain or heart attack as an extension of an allergic reaction.  Kounis syndrome is caused by mast cell activation causing vasospasm of the coronary artery.  It is not known if the mast cells effecting this pathology are normally developed mast cells or improperly developed, such as seen in mastocytosis and MCAS.  This syndrome accounts for about 0.002% of all acute heart attacks.  (An in depth post on Kounis syndrome is on the way.)
MCAS patients often experience coronary and peripheral atherosclerosis.  Some have pain due to narrowing of the vessels.  Sclerosis and poor healing is seen in many MCAS patients.  Due to the importance of mast cells in angiogenesis, long term mast cell activation can contribute to aneurysms, hemorrhoids, varicosities, hemangiomas, arteriovenous malformations and telangiectasias. 
Edema is a common finding.  Most MCAS patients who have edema have no heart abnormalities and do not have pitting edema, indicating that the edema is likely not from heart disease.  MCAS patients often have widespread edema that can shift to different parts of the body.  There is usually no detectable low albumin.  This is thought to be due to third spacing. 

References:
Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011; 4:10-17.
Ribatti D, Crivellato E. Mast cells, angiogenesis, and tumour growth. Biochim. Biophys. Acta Mol. Basis Dis. 2012 Jan; 1822(1): 2-8.
Glowacki J, Mulliken JB. Mast cells in hemangioma and vascular malformations.  Pediatrics 1982; 70(1):48-51.
Ribatti D, Crivellato E. Mast cells, angiogenesis, and tumour growth. Biochim. Biophys. Acta Mol. Basis Dis. 2012 Jan; 1822(1):2-8.
Glowacki J, Mulliken JB. Mast cells in hemangioma and vascular malformations. Pediatrics 1982; 70(1):48-51.
Kolck UW, Alfter K, Homann J, von Kügelgen I, Molderings GJ. Cardiac mast cells: implications for heart failure. JACC 2007 Mar 13; 49(10):1106-1108.

The speed of falling apart

I saw my GI mast cell specialist today.  I have not been looking forward to this appointment.  I find that whenever the shit hits the fan with my health, it is always him telling me things I don’t want to hear in the small exam room at the end of hall. 

I am having major GI issues.  I am nauseous.  I vomit up most of what I eat.  I am reacting not just to food, but to the actual process of eating.  Beyond this, I have had a major change in lower GI symptoms.  I am bleeding from multiple places and spending a lot of time in the bathroom.  My abdomen is swollen and sore again.  If I lay back, I can literally watch myself digesting. 
We went through all my symptoms.  I told him about my endocrinologist appointment and filled him in on some conversations with my immunologist.  He examined me and palpated my sore abdomen, could feel that my colon was swollen. 
“Your problem is proliferation,” he said.  “If you started with two million mast cells, now you’ve got a hundred. Or more.”  I know.  I didn’t have anything helpful to add.  I really hate when I can’t pull useful more information out of my brain because it doesn’t exist. 
I already have a good surgeon, so he agreed to talk to him and get back to me on who wants to order what.  I will definitely need another colonoscopy with biopsies, at the very least, before they decide what to do for surgery.  He called my GI distress “incredible troubles.”  I laughed when he said it.  “Your troubles, they are incredible,” he clarified.  “A lesser person might not do so well.” But I didn’t feel like I was doing well today.  I wanted to go to sleep, quiet and numb, for as long as I could. 
I have said several times that this has been a strange year.  I feel like I can’t express what I mean by that properly.  While I have gotten sicker this year, I have at the same time found an increasing sense of peace.  I feel like I am helping people, and that was only possible because I am sick.  I learned about mast cell disease because I am sick, and I met all these people because I am sick, and I like this life, that I have because I am sick.  All of this is a side product of being sick. 
I skyped with one of my best friends tonight.  “I feel so guilty because I love what I do and I love all these people but it’s all because I’m sick and I don’t want to be sick anymore,” I cried to her.  I had a good long cry.  It was one of those days. 
But in the dark moments, when it feels like my soul is trying to swallow itself whole, I remember this year, and how as time goes on, I somehow feel less and less at odds with my disease.  I somehow feel the anger subsiding, feel this overwhelming calm as I learn how to live in this body each day. 
This year has been weird.  I am self actualizing at the speed of my body falling apart.

Mast cells and metabolic syndrome: Hypertension, obesity and atherosclerosis

Metabolic syndrome is defined as impaired glucose tolerance (IGT) or type 2 diabetes and/or insulin resistance with two or more of the following findings:

1.       Abdominal obesity, defined as a BMI ≥30; and/or waist to hip ratio >0.90 in men and >0.85 in women
2.       Baseline blood pressure >160/90 mm Hg
3.       Increased plasma triglycerides >1.7 mmol/L; and/or low levels of HDL cholesterol (<0.9 mmol/L in men; <1.0 mmol/L in women
4.       Microalbuminuria (overnight urinary albumin excretion rate > equal to 20 ug/min.)
Inflammation is a known effector of obesity.  Microscopic examination of obese adipose tissue reveals chronic inflammation and excessive amounts of white blood cells, leukocytes.  Macrophages, white cells that are very important in the inflammatory response, are found in adipose tissue in numbers that are directly proportional to the degree of obesity.  T cells, other white cells, also accumulate in adipose tissue. 
Until recently, most of the research on inflammatory cells in adipose tissue focused on macrophages and T cells.  However, we now know that mast cells congregate in larger than normal numbers in white adipose tissue in obese patients.  These patients also demonstrate a higher serum tryptase concentration than in lean individuals.  Mast cells are usually found near microvessels, very small blood vessels, in white adipose tissue.  The number of microvessels correlate with mast cell count in the tissue, implying that a relation between the microvessels and mast cells.
Mast cells release many chemicals, including TNF (tumor necrosis factor.)  TNF is known to mediate insulin resistance, and is overexpressed in white adipose tissue in obese patients.  Treatment with TNF blockers in patients with inflammatory diseases has demonstrated a significant reduction of blood insulin levels as well as the insulin/glucose index.  Several other mast cell mediators contribute to insulin resistance in fat cells, including IL-6, iNOS, MCP-1 and IL-1. 
Research has shown that mast cell stabilizers, cromolyn and ketotifen, can prevent diet induced obesity and diabetes.  In mice, these medications have been able to reverse obesity and diabetes, as well as reducing body weight and glucose intolerance.  These findings have been very exciting for mast cell patients with diabetes.
It is important to know that while metabolic syndrome is usually associated with obesity, patients of normal weight may also be insulin resistant and have metabolic syndrome.
Hypertension (high blood pressure( in mast cell disease is a topic of a lot of recent debate.  In spontaneously hypertensive rats (SHR), the density of cardiac mast cells is significantly higher than normal immediately after birth.  Throughout life, cardiac mast cell density is much higher in these rats than in controls of the same age.  Mast cell chemicals TNF, NF-kB and IL-6 were overexpressed in these rats even before they became hypertensive.  In later stages of hypertension, hearts of these rats showed increased areas of fibrosis in the heart.  These areas of fibrosis were full of activated mast cells.  Expression of two mast cell chemicals, TGF-B1 and bFGF (basic fibroblast growth factor) is much higher than normal in aging and failing hearts in spontaneously hypertensive rats. 
Importantly, mast cell stabilizer nedocromil was able to prevent fibrosis in SHR rats.  Tryptase levels were elevated in SHRs that were not receiving treatment, but returned to normal after treatment with nedocromil.  In untreated SHRs, levels of interferon gamma and IL-4 were elevated, while IL-6 and IL-10 were lower than normal.  All of these levels normalized after treatment with nedocromil.  This medication also prevented macrophage infiltration in the heart ventricle.  This finding indicates that mast cell signaling to macrophages is an important process in fibrosis.
Atherosclerosis is the accumulation of low density lipoprotein (LDL) cholesterol in the arterial wall.  Macrophages eat particles of LDL, and when they do, they turn into weird looking cells called foam cells.  Mast cells often live very close by foam cells, and many researchers think that mast cells help macrophages transform into foam cells. 
When mast cells release chemicals, chymase and carboxypeptidase A are bound to heparin.  After release, these components form insoluble granules called remnants.  When mast cells are activated, LDL uptake by macrophages rises by 7-24X.  Treatment with cromolyn has been shown to block mast cell dependent LDL uptake by macrophages. 
HDL passes from the bloodstream into the arterial wall.  When mast cells degranulate, those remnants degrade HDL components in the blood, peritoneal fluid and maybe also in atherosclerotic lesions.  Mast cell deficient mice have lower serum total cholesterol, triglycerides, phospholipids and a less atherogenic lipoprotein profile in general.
Mast cells are heavily involved in obesity, hypertension and atherosclerosis.  For this reason, many mast cell patients have these problems. 

Reference:

Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.

Metabolic issues associated with MCAS

MCAS patients often have a whole host of metabolic irregularities.  Abnormal levels of electrolytes are very common, as are mild increases in liver function tests, including aspartate transaminase, alanine transaminase and alkaline phosphatase.  Magnesium levels low enough to cause symptoms is not common, although the reason for this is not known.
Vitamin D deficiency is often present in MCAS.  In one study looking at children with asthma, low vitamin D was correlated with decreased lung function and exercise sensitivity.  In MCAS patients, there is no obvious relation to osteoporosis.  Many people receive vitamin D supplements to correct low levels, but it is not clear if there is any benefit to this.

Hypothyroidism (including Hashimoto’s thyroiditis) and elevated levels of TSH are often seen in MCAS patients.  Previous studies have linked hypothyroidism to increased mast cells in bone marrow.  In mice, TSH has shown to increase both the mast cell population in the thyroid and to trigger degranulation.  Hyperthyroidism is sometimes seen in MCAS patients, but much less frequently.  Antithyroid antibodies (TPO) are often high, sometimes extremely high, and sometimes without obvious clinical thyroid disease.

Hyperferritinemia is not unusual in mast cell disease, including MCAS.  18% of ISM patients have high serum levels of ferritin.  It is often misinterpreted as hemochromatosis, even in the absence of the HFE mutation.  MCAS patients with a history of red cell transfusion are often told they have hemosiderosis, even when serum ferritin is much higher than to be expected from hemosiderosis.  High ferritin in MCAS patients is probably secondary to systemic inflammation.  The widely variable nature of the ferritin levels is indicative of inflammation.
MCAS is also associated with obesity and diabetes mellitus (types I and II), all of which are systemic inflammatory conditions.  MCAS patients often have lipid abnormalities.  Hypertriglyceridemia is the most common presentation, but there are many variations.  Lipid issues that have been resistant to treatment with statins are often reversed quickly when MCAS patients are effectively managing their mast cell issues. 
MCAS is also heavily associated with metabolic syndrome.  (There will be a full post on this tomorrow.)

References:
Afrin, Larry B.  Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
A Melander, C Owman, F Sundler.  TSH-induced appearance and stimulation of amine-containing mast cells in the mouse thyroid.  Endocrinology, 89 (1971), pp. 528–533

Siebler T, Robson H, Bromley M, Stevens DA, Shalet SM, Williams GR.  Thyroid status affects number and localization of thyroid hormone receptor expressing mast cells in bone marrow.  Bone. 2002 Jan;30(1):259-66.

Chinellato I, Piazza M, Sandri M, Peroni DG, Cardinale F, Piacentini GL, Boner AL.  Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma.  Eur Respir J. 2011 Jun;37(6):1366-70. 

Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.

Genetics of MCAS: mutations and methylation

Despite having largely the same symptom profile as SM patients, people with MCAS often lack the signature D816V mutation, considered by many to be a marker of clonality and thus proliferation.  Despite the fact that their mast cells may look normal under a microscope, there is now a growing body of evidence indicating that mast cells in MCAS patients behave aberrantly due to mutations aside from D816V. 
In three studies that look at KIT mutations in MCAS patients, they were found in 26.5%, 44% and 65% of patients, respectively.  Even the average of these three values represents a significant number of people with MCAS who have KIT mutations.  Of note, these mutations are mostly outside of exon 17, where the D816V mutation is found.  In one patient, a mutation was found in the NLRP3 gene, associated with the inflammatory response. 
There are a number of other mutations in genes with various functions commonly found in patients with SM.  These include genes that make proteins to regulate other genes and genes that affect how we make proteins (epigenetic regulatory proteins, splicing machinery and transcription factors.)  To date, there have been no studies looking at whether MCAS patients have similar mutations.  However, there are clear hints that they do. 
The mutations previously mentioned were all somatic and not germline.  This means that the mutations arose after early embryonic development and thus were not heritable.  This fact indicates clearly that there are other germline mutations not yet identified that may induce the subsequent mutations.  This has been bolstered by a 2013 paper that found familial clustering in MCAS patients.   
An important finding is that nearly all mutations found in MCAS patients are heterozygous, meaning only one of the two copies was mutated.  This implies that homozygous mutations, in which both copies are mutated, could cause the cell to die.  Alternatively, the various mutations may work together to make the mutations work as strongly as if there were two mutated copies. 
At CpG sites, the cell can add a special marker to the cytosine called a methyl group.  This is called methylation.  If the cytosine in a gene is methylated, it turns the gene off.  When a gene is turned off, your body will not use that gene or make a protein from it.  This is one type of gene regulation (epigenetics.) 
Looking at the methylation status in the genomic DNA of white blood cells from MCAS patients shows aberrant methylation patterns.  The genes incorrectly methylated included some involved in DNA/RNA repair, DNA/RNA processing, cell death, cell activity and communication with other cells.  195 individual CpG sites have been identified as candidates as markers for MCAS.  Importantly, there is a correlation between the age of symptom onset and the year of birth, which indicates a sort of anticipation of developing MCAS.  This means that gene regulation by methylation could affect acquisition of later, non-heritable mutations like the ones seen in KIT.
A gene is made up of introns and exons.  When an RNA code is made from a gene to tell the cell how to make a protein, the cell cuts out some pieces of that RNA.  These pieces are called introns.  The remaining pieces, which are connected back together, are called exons.  The way the cell cuts the RNA and reconnects the pieces is called splicing.   The mutations in KIT seen in MCAS patients almost all involve intron and exon junctions, where they meet.  There are also some differences in the way splicing occurs in MCAS patients. 

Reference:
Molderings, Gerhard J.  The genetic basis of mast cell activation disease – looking through a glass darkly.  2014.  Critical Reviews in Oncology/Hematology.

Constitutional symptoms of MCAS


Constitutional symptoms are any symptoms that affect the function of several systems at once.  They are often nonspecific and can be attributed to many causes, complicating diagnosis. For many people with MCAS, the constitutional symptoms present first and with the greatest frequency.

Fatigue and malaise (the feeling of being “out of it”) are the most common symptoms reported in MCAS patients.  While many patients with these symptoms remain functional, for some, it can be truly, severely disabling, with some patients sleeping for the majority of the day.  Dr. Afrin has referred to stories of “patients in their twenties acting like they are in their eighties.”  Chronic fatigue syndrome, in which patients have severe fatigue unrelated to exertion, not relieved by rest and unrelated to other medical conditions, has been tentatively linked to mast cell activation by Dr. Theoharides. 

I see a lot of discussion about whether or not fevers are part of MCAS.  It depends which researcher is reporting information.  Castells feels strongly that fevers are not part of MCAS symptomology, while Afrin and Molderings feel that they are.  They report that intermittent elevated temperatures are not unusual.  These temperatures are low-grade temperatures, with frank fever being quite rare.  MCAS patients often report constantly feeling cold, though chills and shaking is less common.

I know that one of the ways I can tell my mast cell disease is ramping up is by severe night sweats.  This is apparently common in most presentations of mast cell disease.  As such, many MCAS patients have severe, unprovoked sweating, often overnight, sometimes not.  Some patients report a circadian rhythm.  Furthermore, this sweating is often accompanied by swollen or tender lymph nodes.  When these two symptoms are taken together, usually infection or lymphoma is suspected.  Once these are ruled out, patients are often left with no relief for this frustrating symptom.

Some patients report lack of desire to eat.  Some report quickly feeling full (early satiety.)  In some of these patients, the root cause is a swollen spleen.  A minority of MCAS patients lose weight due to their disease.

Weight gain in MCAS patients is far more common than weight loss.  It often begins suddenly and progresses rapidly, in the absence of dietary or activity changes.  This is partially due to the fluid dynamics of edema due to mast cell activation.  Less often, weight gain is from ascites (free fluid in the abdomen) or serositis, inflammation of the serous tissues, including the pleura (tissue lining the lungs), pericardium (the compartment containing the heart and origination of the large vessels connecting to the heart) and the peritoneum (tissue lining the abdomen.) 

However, the gain in adipose (fat) tissue seems to be responsible for most of the persistent weight gain.  Some patients gain more than 50kg in a year despite significant caloric restriction and frequent exercise.  Many people (and their providers) often attribute their worsening symptoms to the gained weight.  Some people undergo bariatric surgery and despite initial losses, regain the weight, with no improvement of other symptoms.

Pruritis (itching) is very common in MCAS.  Its presentation is varied; episodic or constant; local or diffuse; migratory or not; tolerable or disabling.   

The hallmark of MCAS is that patients invariably present with a collection of “sensitivities.”  These include severe or bizarre reactions to virtually anything, including drugs, food and environemental triggers.  Environmental triggers can be due to the presence of common allergens, physical (such as heat), electrical (such as generation of electrical charge when brushing hair) and even osmotic.  Exposure to harmless microorganisms can cause severe reactions.  Summers are often difficult for MCAS patients due to heat and increased UV exposure, while spring and fall are difficult due to pervasive pollen.  Triggers can cause reactions when the patient touches, inhales or ingests them. 

Though less of a problem than heat, exposure to cold can trigger a hyperadrenergic response that will fuel mast cell activation.  Care must be taken to avoid temperature extremes on either end of the spectrum.

Drug sensitivities are often found to be due to an inactive ingredient in the formulation.  Compounding is an important tool for MCAS patients.  Lactose monohydrate and potato are common fillers for MCAS patients.  Reconstitution at time of use with water is also not uncommon.

 

Reference:

Afrin, Lawrence B.  Presentation, Diagnosis and Management of Mast Cell Activation Syndrome.  2013.  Mast Cells.