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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

Language matters: Mast cell terminology

This is by no means a comprehensive list – just a review on definitions of some commonly confused terms.

Acute: This word gets used a lot when people mean “severe.” Acute does not mean severe. It means sudden onset or having a short, limited course. For example, stage III anaphylaxis is an acute complication of mast cell disease. Its symptoms come on suddenly, require immediate treatment, and once treated, resolves. (I am not referring to the after effects of anaphylaxis – just the emergency and treatment.) In a medical sense, acute is the opposite of chronic.

Chronic: Long term, occurs all the time, is expected to occur forever. I have mast cell disease and am chronically ill. I have acute anaphylactic emergencies.

Progressive: Getting worse or will get worse. This term gets used loosely by patients to mean that their symptoms get worse. Medically speaking, this generally refers to progression of disease from one stage to the next, like SM to ASM. SM and MCAS are not inherently progressive diseases. People who have progressed from SM to SSM or ASM have progressive disease.

 

Systemic symptoms: Any symptoms that do not involve the skin. Can be present in cutaneous mastocytosis or MCAS. So diarrhea is a systemic symptom. Tachycardia is a systemic symptom. Systemic symptoms do not mean you have SM.

Systemic mastocytosis: the diagnosis you receive if you meet either the major criterion listed subsequently and at least 1 of the 4 minor criteria, or at least 3 minor criteria if the major criterion is not met:

Major criterion

Multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organ(s)

Minor criteria

In biopsy sections of bone marrow or other extracutaneous organs, >25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology, or, of all mast cells in bone marrow aspirate smears, >25% are immature or atypical

Detection of an activating point mutation at codon 816 of KIT in bone marrow, blood, or other extracutaneous organ

Mast cells in bone marrow, blood, or other extracutaneous organ express CD2 and/or CD25 in addition to normal mast cell markers

Serum total tryptase persistently exceeds 20 ng/mL (unless there is an associated clonal myeloid disorder, in which case this parameter is not valid)

The diagnosis of SM is unrelated to the symptoms the patient experiences. Some SM patients have no symptoms. Some have severe symptoms.

Systemic symptoms ≠ systemic disease (SM)

 

Aggressive symptoms: Frequent or severe symptoms, which may be life threatening.

Aggressive disease: Doctors sometimes use this term to mean a quick progression of symptoms or rapid change in quality of life.

Aggressive systemic mastocytosis: A diagnosis that indicates multiple organ infiltration and damage by mast cells. Lifespan is significantly shortened in many patients. It is diagnosed by already meeting the criteria for SM and then also having at least one C finding, listed here:

Bone marrow dysfunction manifested by one or more cytopenia (ANC < 1.0 × 109/l, Hb < 10 g/dl, or platelets < 100 × 109/l), but no frank non-mast cell haematopoietic malignancy

Palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension

Skeletal involvement with large-sized osteolysis and/or pathological fract

Palpable splenomegaly with hypersplenism

Malabsorption with weight loss due to GI mast cell infiltrates

Aggressive symptoms and aggressive disease ≠ aggressive systemic mastocytosis (ASM)

 

Smoldering systemic mastocytosis (SSM): A progression from SM with markers that indicate likelihood of developing ASM. Diagnosed if two or more of the following B findings are present with previous diagnosis of SM:

Bone marrow biopsy showing > 30% infiltration by mast cells (focal, dense aggregates) and/or

serum total tryptase level > 200 ng/ml

 

Signs of dysplasia or myeloproliferaion in non-mast cell lineage, but insufficient criteria

for definitive diagnosis of a haematopoietic neoplasm by WHO, with normal or only slightly

abnormal blood counts

 

Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without

hypersplenism, and/or palpable or visceral lymphadenopathy

 

MCAS: Differing criteria among experts

What criteria you have to meet to be diagnosed with MCAS depends on which doctor you see – even the experts don’t agree.

Molderings, Afrin 2011 Akin, Valent, Metcalfe 2010 Valent, Akin, Castells, Escribano, Metcalfe et al 2012
MCAD (umbrella term including both MCAS and SM) diagnosed if both major criteria, or one major criterion and one minor criterion, are present; following bone marrow biopsy, diagnosis is narrowed down to either SM or MCAS MCAS diagnosed if all criteria are met MCAS diagnosed if all criteria are met

Major Criteria
Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained)
Episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems evidenced as follows:
  1. Skin: urticaria, angioedema, flushing
  2. Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
  3. Cardiovascular: hypotensive syncope or near syncope, tachycardia
  4. Respiratory: wheezing
  5. Naso-ocular: conjunctival injection, pruritus, nasal stuffiness
Typical clinical symptoms
Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom) A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1– and H2-histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period
  Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2. Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn
  Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities

Minor Criteria
Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
Mast cells in bone marrow express CD2 and/or CD25
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
Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  1. Tryptase in blood
  2. N-methylhistamine in urine
  3. Heparin in blood
  4. Chromogranin A in blood
  5. Other mast cell specific mediators (leukotrienes, PGD2)

MCAS: GI Symptoms and Liver Abnormalities

MCAS patients suffer a variety of GI ailments, which are largely in common with SM.

Aerophagia, excessive swallowing of air, is very common. It is not entirely obvious why this occurs. In other patient populations, aerophagia is usually due to poor coordination between swallowing and respiration. Severe cases can lead to abdominal distention, aspiration of stomach contents into the lungs and esophageal rupture.

Chest discomfort is common in MCAS. Cardiac issues should be ruled out, but in most people, it is due to esophagitis. Some patients have a previous diagnosis of reflux but it is refractory to all relevant treatments.

Diarrhea and constipation, sometimes alternative, are very common. In one study, 89% of MCAS patients studied had frequent nausea, 100% had abdominal pain of some nature, and 69% had noncardiac chest pain. Partial bowel obstructions are uncommon, but do occur in MCAS. They are thought to be due to focal dysmotility or focal edema.

IBS is a frequent previous diagnosis in MCAS. The GI tract often looks normal by eye and typical H&E staining shows mild inflammation. Staining for mast cells often shows they are increased. Of note, there is not a universal consensus on what is considered “increased mast cells” in GI samples. Generally, above 20 cells per hpf is marked as high by pathologists. Presence of the D816V CKIT mutation is rare in GI biopsies of MCAS patients.

Selective malabsorption of certain nutrients is often seen in MCAS. Iron malabsorption is by far the most common. Copper and B vitamins are often poorly absorbed as well. Protein calorie malabsorption is rare, but leads to weight loss and wasting.

Pancreatic enzyme supplementation can be helpful in treatment of diarrhea, weight loss and malabsorption. The fact that this often works suggests that MCAS driven inflammation or fibrosis causes pancreatic exocrine deficiency, a condition in which the pancreas does not make enough digestive enzymes. Mast cells have a known link to painful chronic pancreatitis. In patients with painful vs painless chronic pancreatitis, mast cell density is 3.5X higher in pancreas biopsy.

About half of MCAS patients have some kind of liver abnormality. Fibrosis (obliterative portal venopathy) is the most common. However, fatty metamorphosis, sinusoidal dilatation, venoocclusive dilatation, nodular regenerative hyperplasia and cirrhosis have also been seen. Sterile (non-infectious) inflammation of the liver and portal trial infiltration by lymphocytes and eosinophils has also been identified in a number of patients. In particular, these patients often have a 2-3X elevation in transaminases and/or alkaline phosphatase, determinants of liver function. Impeded flow of bile from the liver is usually absent. Portal hypertension is unusual but has occurred, causing swelling of the spleen and varices in the esophagus. Rarely, free fluid in the abdomen (ascites) has occurred in MCAS patients.

One study found that 75% of MCAS patients tested had high cholesterol levels. Importantly, 79% of patients had “normal” BMI or were underweight, so the high cholesterol was not correlated to weight. 44% had a twofold or greater elevation of liver enzymes. 36% had increased bilirubin in the blood. 15% had fatty liver; 13% had swelling of the liver; 4% had cysts; 4% had adenomas; 2% had hemangiomas. 14% of patients had pancreatic involvement with elevated lipase or amylase.

 

References:

Kirsten Alfter, Ivar von Ku gelgen, Britta Haenisch, Thomas Frieling, Alexandra Hu lsdonk, Ulrike Haars, Arndt Rolfs, Gerhard Noe, Ulrich W. Kolck, Jurgen Homann and Gerhard J. Molderings. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. 2009 Liver International 29(2): 181-186.

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2011. Mast Cells.

MCAD: General information for public

Mast Cell Activation Disorders (MCAD): Frequently Asked Questions

What are mast cell activation disorders?

They are a group of conditions  in which the mast cells in the body do not function correctly.  MCAD includes systemic mastocytosis, urticaria pigmentosa and mast cell activation syndrome, among other conditions. Mast cells are responsible for allergic responses. In MCAD, patients can have allergic type reactions to things they are not allergic to. These reactions can be very severe and even life threatening.

What are mast cell reactions?

These are reactions caused by mast cells being improperly activated. These reactions vary from person to person. Symptoms can include, but are not limited to, nausea, vomiting, hives, rashes, itching, flushing (turning red), dizziness, confusion and irritability. Symptoms are caused by the chemicals released by the mast cells.

What causes mast cell reactions?

Triggers vary from person to person. More common triggers include heat, cold, friction (especially on the skin), sunlight, foodstuffs, physical exertion, stress, dyes and fragrances. Triggers can also change over time, with new triggers presenting.

Are mast cell reactions dangerous?

YES. Many MCAD patients will experience uncomfortable reactions throughout their lives. However, every reaction carries the risk of anaphylaxis, a life threatening, severe allergic reaction. Therefore, avoiding reactions as much as possible is very important for mast cell patients. Each patient has an individualized response plan. For many, it involves removal of trigger and administration of medication, such as antihistamines or inhalers.

What is anaphylaxis?

Anaphylaxis is a severe allergic reaction affecting multiple organ systems in the body. These are the kinds of reactions observed in patients with bee sting allergies. Anaphylaxis can be fatal. It is a medical emergency requiring immediate treatment, usually epinephrine (Epipen.) Please receive guidance from treating physician on when to use an Epipen.

How are mast cell anaphylaxis and mast cell reactions different from normal allergies (like food allergies?)

With allergies, your body reacts by a specific method that involves ingesting and recognizing the allergen. In MCAD patients, the mast cells incorrectly think many things are allergens. Since mast cells are so sensitive in these people, ingestion of an allergen is NOT necessary to cause mast cell reactions or anaphylaxis. Smelling a perfume or breathing in very hot, humid air is enough to cause a reaction in many MCAD patients.

What causes MCAD?

Genetic mutations cause different kinds of MCAD. Recent studies have shown that mast cell disease can affect multiple members of the same family.

Why do some MCAD patients have spots?

These spots occur in locations where there are more mast cells than usual in the skin. These are NOT contagious rashes. In addition, MCAD patients who do not have permanent spots often have very sensitive skin, which may cause temporary marks or rashes.

How can I help an MCAD patient be safe?

By not being afraid of their disease. Respect their triggers and help them work around these limitations. Reactions can be painful and very scary, especially for kids. Learn the symptoms associated with reactions and be ready to help with a response plan.

 

Is there more information you feel should be included here?  Let me know in the comments and I can add it in.

Lost in space

One of my most deep seated irrational fears is being lost in outer space. Being lost, alone, surrounded by this vast expanse of loneliness – that is the fabric of my nightmares.

“If you die in space, your body just keeps moving until something hits it. Then the pieces keep moving. It doesn’t decompose,” I remember my middle school science teacher telling me. My revulsion was immediate and visceral. It seemed so unkind that space didn’t even offer this last kindness, the ability to disappear and be forgotten. You would be all alone, with no chance of help, and when you die, your body will memorialize this helplessness and despair, forever.

It feels hollow and soundless when I think about space – the ultimate loneliness. Sometimes when masto is too much and I am tired of living in a world that isn’t safe for me, I hide in bed with my feelings, and they are hollow and soundless, too.

A woman I sort of knew killed herself this morning. She had a young son with mastocytosis, and I knew her in the way I know many masto parents – I answered questions for her. I knew very little about her or her family or her own poor health. But her death has started a larger conversation about support that I think needs to be had, and I think we owe it to this woman to have it now. Because even if lack of support was not the reason she ended her life, it is definitely the reason many people in our community have contemplated doing the same.

Let’s pretend that you, my audience, are healthy. Let’s pretend you don’t have any chronic health issues. You’re walking down the sidewalk one day, listening to music on your Iphone and get hit by a car. You are taken by ambulance to the hospital and are relieved to find out that while your leg is broken, you are otherwise okay. Your leg needs some surgery and a cast and you will be good as new soon. You have your surgery and you go home.

Except what if eight doctors looked at your xray and told you your leg wasn’t broken but you could feel the bones shifting? What if you couldn’t bear weight on it, if your pain was excruciating, but they insisted you were fine? What then? What if you went home and stayed off your leg until you could figure out why it hurt only to be called lazy and lucky to be able to stay in bed all day? What if your spouse was upset that your leg hurt too much to move around the kitchen and cook dinner? What if your family members told your kids that your house was dirty because you were lazy and making up the pain in your leg? And what if you find a doctor who sees something on your xray and agrees to work with you, but your family tells people this was all your fault for going for a walk that day or listening to music or being outside? What if the people around you not only denied your condition, but actively refused to support you? What if they made you feel guilty not being unwell as if your sickness was your fault?

This is what life is like for a lot of mast cell patients. I hear from patients all the time that their spouse doesn’t believe they are really sick. I hear that their mother told their kids that they are lying. And for parents of sick kids, I often hear that one parent won’t acknowledge or learn about their kids’ disease. It is discouraging and horrifying and dangerous. Because just like ignoring a broken leg won’t make it heal, pretending someone doesn’t have mast cell disease won’t make them any less sick. It will just make them more alone.

I’m fed up with watching people I care about struggle with family members, friends, coworkers, etc, who feel that acknowledging and accommodating their disease is too much to ask for. I’m tired of my friends crying for support when they are alone in the ICU, going into shock in their home, because their family members won’t help them. This is abuse. No one deserves this.

To everyone who has a chronically ill person in their lives: If you are not helping, you are hurting. When you tell us we are faking or being dramatic or exaggerating, you are chiseling off little slivers of our being that we will never get back. You remind us that we are not worthy of help and sympathy in your eyes. You force us to stop asking for your support, until sometimes it becomes too much. Sometimes when you scream for so long and no one cares, suicide can seem like a relief.

I am very lucky to be well supported now, but I know the pain of begging someone to take care of you. It feels like a great dark expanse, weightless, silent and endless.

 

MCAS: Treatment

This post discusses medications used to treat MCAS. Doses listed are taken directly from “Presentation, diagnosis and management of mast cell activation syndrome” by Lawrence B. Afrin. These doses are general recommendations. Medication should always be taken under the direction of a provider who knows you and your case personally.

MCAS is generally treated identically to ISM, with the medications that block the action of released mediators, that prevent the release of mediators or that prevent the production of mediators. As a reminder, any medication that causes a reaction should be evaluated to see if it is truly caused by the drug or by a dye or inert ingredient. Medications compounded without dyes or noxious fillers can be truly life changing for mast cell patients. Generally, new medications for be trialed for 1-2 months to determine if they are effective.

Antihistamines are first line medications for both acute and chronic management of MCAS (but not for anaphylaxis – epinephrine is first line medication for anaphylaxis.) Most currently available antihistamines either block the histamine 1 (H1) receptor or the histamine 2 (H2) receptor and are referred to by the receptors they block. It is generally recommended for MCAS patients to take medication to block H1 and H2 receptors daily as baseline medications.

Loratadine is a common H1 starting medication. It has low anticholinergic activity and is not sedating. Dosing usually starts at 10mg daily and may be increased to 10mg 2-3 times a day. Fexofenadine starting dose in MCAS is usually 180mg every 12 hours; cetirizine 10mg every 12 hours; levocetirizine 5mg every 12 hours. Loratadine, fexofenadine and cetirizine are all available without prescription in the US. Of note, none of these medications are available for IV administration, so Benadryl should be used for emergency management of severe MCAS symptoms.

There are several H2 blockers available in the US, most over the counter. Cimetidine and ranitidine have more drug-drug interactions than famotidine and nizatadine. Famotidine, which is also readily sourced for IV administration, is usually dosed at 20-40mg every 12 hours, though in severe cases, doses of 80mg every 12 hours may be used. (This dosing is also seen in Zollinger-Ellison Syndrome patients.) Ranitidine starts at 75mg every 12 hours, increasing to 300mg every 12 hours. Nizatadine (Axid) is dosed at 150-300mg every 12 hours, and cimetidine at 400mg every 12 hours.

There are several other medications with H1 antihistamine effect. Tricyclic antidepressants, phenothiazine antiemetics (like promethazine) and quetiapine, an antipsychotic, are all H1 blockers. Addition of these medications often helps even when another H1 blocker is being taken by the patient. In particular, use of doxepin has been well described. It is usually started at 10mg twice daily and can be increased by 10mg twice daily to doses of 40-50mg twice daily. Beyond this, exhaustion and grogginess are often intolerable.

Ketotifen is a medication with both antihistamine and mast cell stabilizing properties, meaning it interferes with the release of mediators. The oral use of this medication for mast cell disease management is not well described, in part due to the oral formulation not being available in the US. Dosing is usually started at 1mg twice daily and increased in increments of 1mg twice daily until desired effects are noted and balanced with an acceptable side effect profile. As described by Afrin, single dosing is usually 6mg or less, and can be taken up to four times a day.

Benzodiazepines are often helpful in MCAS, due both to its action on mast cells and also directly on organs, particularly GI organs. Lorazepam, clonazepam and alprazolam are preferred due to their shorter window of action. All can be dosed beginning at 0.25mg every 12 hours, increasing by 0.25mg twice daily every week. Flunitrazepam has been described in treatment of mast cell disease. This medication has a longer halflife and is generally dosed at 0.5-2mg once a day.

Imidazopyridine medications like zolpidem (Ambien) also act on the benzodiazepine receptors of the body. Though usually taken for insomnia, some MCAS patients report relief of other symptoms. Whether or not these medications work in a patient seems independent of whether benzodiazepines are currently being taken by the patient or have worked or failed in the past.

Non-steroidal anti-inflammatory drugs (NSAIDS) can be helpful in MCAS patients who tolerate them. In particular, use of aspirin to bind prostaglandins has been very well described. A common starting dose is 325mg twice daily, with dosing up to 650-1300mg twice daily seen. Some patients take as much as 1300mg four times a day, but doses higher than 2600mg/day are unhelpful in most patients. Non enteric coated aspirin seems to be better tolerated and more effective at relieving symptoms in MCAS than enteric coated. In MCAS patients for whom aspirin is inappropriate (such as those with low platelets or decreased kidney function), COX2 inhibitors like Celebrex are sometimes used. Celebrex dosing in these patients usually begins at 100mg twice daily and increases up to 400mg twice daily.

Leukotriene inhibitors are frequently used in MCAS patients. Montelukast is the most common, being dosed as 10mg once to twice a day. Zafirlukast is dosed at 20mg twice daily. Doses should be decreased appropriately if liver dysfunction is also present.

Cromolyn is the most well known mast cell stabilizer, despite the fact that the mechanism by which it acts is still unclear. More recently, it has been noted to block mast cell receptor 35, which is increased when IgE is present. Cromolyn has extremely poor absorption, with 98% of oral doses being excreted unchanged. When inhaled, absorption increases to around 5%. Oral dosing is from 100-200mg 2-4 times daily. When nebulized, dosing is usually 20mg 2-4 times daily. Of note, patients usually experience a resurgence of symptoms when first starting the medication that may last 3-4 days. In my experience, this symptom increase is sometimes observed when increasing the dose. It can take several weeks to determine if cromolyn is truly effective in patient, with some people only seeing serious gains after four months.

Pentosan is less well known mast cell stabilizer whose mechanism is likewise unknown. This medication is commonly used in interstitial cystitis, a mast cell disorder that affects the genitourinary tract. Though Pentosan seems to be most effective in the GU tract, some patients report decrease in other symptoms while on this medication. It is usually dosed at 100mg every 8-12 hours.

Quercetin is commonly mentioned as a natural/homeopathic mast cell stabilizer. After much research on the topic, I have to say that I agree. It has been found to inhibit lipoxygenase and cyclooxygenase, which in turn decreases production of leukotrienes and histamine. It is usually dosed starting at 500-2000mg per day, divided up into 2-4 doses. For example, a daily dose of 500mg may be taken as 125mg four times a day. A newer form, quercetin chalcone, is usually taken at 250mg three times a day.

Pancreatic enzymes, like Creon, are sometimes helpful in MCAS patients who have pancreatitis symptoms, even if they are not having pancreatic type pain. It sometimes helps with chronic diarrhea, weight loss and malabsorption.

Corticosteroids like prednisone are sometimes used to manage MCAS symptoms.  These medications can prevent mast cells from producing mediators and as such can be very effective.  However, long term use can have severe side effects and as such is discouraged.

Omaluzimab (Xolair) is an anti-IgE antibody. It is not clear exactly how this stabilizes mast cells reacting by a non-IgE mechanism. Xolair is injected subcutaneously at doses of 150-300mg every 2-4 weeks. It should be trialed for at least 3-4 months before determining if it is effective. Interestingly, whether or not a patient responds and how well seems to be independent of their pretreatment IgE level.

The successful use of chemo medications for severe MCAS cases has been described in literature. In particular, hydroxyurea can be effective, though rapid onset and severe low blood cell counts are a real risk. It is usually started at 500mg daily and increased up to 2000mg daily as needed. Blood counts should be monitored weekly for four weeks at the onset of treatment and after any dosage increase. Tyrosine kinase inhibitors, like imatinib and dasatinib, have also been used as last resorts in MCAS patients. Imatinib is usually dosed at 100-200mg daily and dasatinib at 20-50mg daily. Patients on these medications require careful monitoring for pulmonary and renal issues. All chemo patients are at increased risk of infection.

IV hydration is being used more frequently to manage baseline symptoms of MCAS patients. TNF-alpha inhibitors have been suggested to help mast cell symptoms, but there have been no symptoms. (I take a TNF-alpha inhibitor for autoimmune issues and do find it helps to relieve some of my mast cell symptoms.) Other possible avenues include IL-1 and IL-1b inhibitors and kinin-b2 receptor blockers. Tryptase inhibitors continue to be in development.

 

Reference:

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2013. Mast cells.

 

Sorry not sorry – Why I’m calling out singer Natalie Grant

Saturday afternoon, a masto friend reached out to me.  She was upset about a Facebook post by a prominent Christian singer, Natalie Grant.  Ms. Grant posted the following to her Facebook wall on Saturday:
“Such a sweet time in Minneapolis at Women of Faith.  But now it’s on to LAX to continue filming the next episode of It Takes a Church.  And why yes, that is a battery operated essential oil diffuser that I’m using in my airplane seat.  Rocking the thieves oil and keeping the germs away.  And it’s helping the plane to smell much better #sorrynotsorry”
I groaned when I read it.  I actually groaned out loud.  I opened the thread to find mast cell patients commenting that oil diffusers can be dangerous for people like us, that they could trigger anaphylaxis. Grant’s fans argued that these people were just looking for something to complain about, that oils could never harm anyone, that you have to ingest a protein to have anaphylaxis.  The general spirit of their responses was that mast cell patients were just being oversensitive. 
That’s exactly right – but not the way that they mean.  Our bodies experience severe reactions to pretty much anything – and those reactions aren’t in our heads.  The fact that so many people commented that it was impossible for an oil diffuser to present a real health risk to others represents a serious danger to people like myself.  That is why the mast cell community found this so upsetting.
So let’s discuss why this is dangerous for people with mast cell disease.
Mast cell diseases are a group of disorders in which your body either makes too many mast cells, mast cells do not function correctly, or both.  Mast cells are the cells that are responsible for allergic reactions.  For normal people to have an allergic reaction, their body has to make a molecule called IgE that remembers it is allergic to something.  So people with peanut allergies have peanut IgE, and when they eat peanuts, the peanut IgE tells the mast cells to have an allergic reaction. 
People with mast cell disease pretty much skip this step entirely.  We have severe allergic reactions to things we are not actually allergic to.  This includes lots of foods, materials, environmental factors and others.  For some people with mast cell disease, these reactions include unpleasant symptoms that can be managed at home, like nausea/vomiting, skin reactions, headaches.  But some of us have severe, life threatening anaphylactic reactions based upon even very casual exposure to these substances.  These reactions require use of epinephrine (Epipens), IV antihistamines and steroids, and monitoring at the hospital to ensure that we survive.  People with severe mast cell disease can have several of these episodes in a year.  (I had three in 48 hours in May.)
To be clear: anaphylaxis can be fatal.  Mast cell patients are more likely to experience anaphylaxis and more likely to have severe reactions.  Our best protection is to avoid triggers and medicate appropriately, but this isn’t always possible.  Due to the rare and unusual nature of our diseases, there are few specialists worldwide so the vast majority of patients must fly to see them.  Hiding at home all the time with a mask on is both not practical and not an acceptable way to live. 
Every day, people with mast cell disease seek to minimize the damage to their bodies by avoiding triggers as much as possible.  In enclosed indoor spaces, this can be particularly difficult.  Once triggered, the only option is to medicate and end exposure to the trigger.  When flying, this is obviously impossible. 
While mast cell diseases are rare, fragrance sensitivities and asthma are not.  The CDC has stated that some risks of exposure to scents include asthma attacks, allergic reactions, headaches, migraines, sore throats, coughing, eye irritation, and other medical symptoms.  Asthma attacks can be triggered by fragrances in 72% of asthma patients.  Patients with multiple chemical sensitivity often have severe symptoms similar to those mast cell patients experience.  The fact that workplaces are gradually transitioning to be fragrance free environments is indicative of scent exposures negatively impacting the quality of life for many people. 
In an age of increasing allergies and allergic-type reactions, I find that people like me are often at odds with people who feel their personal liberties should not be curtailed.  Many people see this stand against the use of a personal diffuser as an attempt to impose the will of a suffering minority onto the population at large.  They are entitled to feel however they feel.  But as a mast cell patient, this is about allowing us to move as safely through the world as possible.  Is it worth feeling “infringed upon” to not use an oil diffuser in an airplane when it could kill someone?  Literally kill them?
Natalie Grant put up a follow up to the original post the next day.  While it initially looked promising, I was very disappointed.  It includes such gems as, “I am not here to argue about whether pure Young Living essential oils specifically, can harm those with this disease.” And, “I have a niece that is so allergic to peanuts, she can be in the front row of a plane and the person in the back row can open a bag of peanuts and she can go in to anaphylaxis.  However, EVERY TIME she flies, she has to inform the airline and flight attendents of her life-threatening condition.  May I make a suggestion to those who are suffering: be vigilant with airline employees.  DO not allow the plan to take off until the passengers have been informed there is someone on board who has a specific life threatening disease, so please do not use perfumes, lotions, oils, etc while on board the plane today.  No one will be a better advocate than YOU.”
This statement sums up exactly how much Natalie Grant is missing the point.  If I stood up in front of a plane and told people not to use anything scented, they would snicker and still use them because nobody believes we can actually die from a reaction to a scent.  When mast cell patients spoke up to point out that her use of an oil diffuser could be dangerous to us, we were mocked and shouted down.  We are advocating for ourselves.  The problem is that Natalie Grant, and her fans, just aren’t listening. 
And mast cell disease being dismissed publicly by someone with her sphere of influence?  Well, I’d venture my world is even a little bit more dangerous now than it was before Saturday.  So I’m calling her out.  #sorrynotsorry
A succinct presentation that sums up scent related health issues for the general public (along with list of references for above statistics) can be found here: http://www.slideshare.net/J_A_Miller/fragrance-sensitivity-awareness

How to get out of a reaction cycle

If you have mast cell disease, your basic arsenal for managing your disease should include elimination of/ avoidance of known triggers, low histamine diet, second generation H1 antihistamines and H2 antihistamines.  Leukotriene inhibitors, aspirin, mast cell stabilizers, steroids and anti-IgE are also possibilities for maintaining a baseline.
As a mast cell patient, a decent baseline is what you are going for.  A reasonable baseline does not always mean that you can live the same way you did before your diagnosis.  It means that you are somewhat functional on a day to day basis.  What this looks for is different for everyone, but I aim for not being in bed for 20 hours a day, not being in 5/10 pain every day, being mentally coherent.  Most importantly, you should not have to take rescue meds frequently.  If you need rescue meds often, then you are not covering your mast cells well enough with your regular meds.  If you have eliminated triggers, then this usually involves tweaking your meds. 
I’m going to give you my insights on what that looks like, but please keep in mind that any med changes should be discussed with your treating physician.  We are all different people and med dosing can be affected by many factors. 
Part of why mast cell patients are prescribed second generation H1 antihistamines is because they are usually not sedating, have little anticholinergic activity and are, to be honest, pretty safe.  Mast cell patients often take several times the recommended daily dose on medications like loratadine and cetirizine.  (Please note: the daily recommended dose for Benadryl, which is a first generation H1, should be respected – overdosing can have serious consequences.)  So while the average person may take one Zyrtec a day for allergies, a mast cell patient may take 3 or 4 a day.  The same is true for the H2 antihistamines, like ranitidine and famotidine.  It’s not unusual to dose very high on those. 
If you have uncontrolled symptoms on second generation H1 and H2, changing the meds to something else in the same class may help.  Sometimes Pepcid works better than Zantac, or whatever.  Some people find that using one Allegra and one Zyrtec works better than two Allegras.  Consider also that inactive ingredients can be triggering and thus decreasing the effectiveness of a med.
If you have screwed around with H1 and H2 meds and have increased doses, adding leukotriene inhibitors, cromolyn or atypical H1 meds, like promethazine or doxepin, may help.  If that fails, ketotifen helps a lot of people, and anti-IgE (Xolair) has benefited some mast cell patients.  Beyond this, you are looking at things like regular IV fluids, steroids, and less palatable choices.
As I mentioned before, having a good baseline means not using rescue meds regularly.  This is really important to feeling as well as possible.  Serious reactions take a while to recover from, even if they don’t need epi.  So if you’re having one every day, it is impossible to get to your baseline without serious intervention.  The meds used to control serious reactions, including Benadryl, can cause rebound reactions that look like anaphylaxis, but are not anaphylaxis.  Let’s talk about this.
Benadryl can cause rebound reactions for two primary reasons.  The first is because it is a very strong antihistamine and it stops histamine release symptoms really well.  One of the things Benadryl does is it stops mast cells from releasing histamine.  So when it wears off, mast cells tend to release a lot of that histamine at once.  Another release is that Benadryl has very strong anticholinergic action.  When your dose wears off, you can have what’s called “cholinergic rebound.”  This can cause headache, nausea, vomiting, diarrhea, brain fog and other symptoms.  Sound familiar?  This is why people feel “hung over” when their Benadryl wears off.  Second generation H1 antihistamines, like cetirizine and fexofenadine, have almost no appreciable anticholinergic activity so they tend to not have this side effect.
Mast cell patients get hit with the double whammy of sizeable histamine release at the same time as they get hit with cholinergic rebound.  So rebound reactions can feel like anaphylaxis, but they’re not the same thing.  If you take Benadryl every day, you are going to have a rebound reaction every day.  It may not be severe, but this is not uncommonly the culprit in patients who say they always get sick around the same time every day. 
Another reason why it is generally not recommended for mast cell patients to take Benadryl every day is because it can stop working.  This is called tachyphylaxis and it basically means your body gets used to it.  When you need to use epinephrine, you are counting on Benadryl and steroids to help control the effects of anaphylaxis on your body.  Patients in whom Benadryl is ineffective get into very dangerous situations when they anaphylax.  I have a few friends like this and it is seriously not pretty. 
It is possible for anaphylaxis to be biphasic or protracted.  Biphasic reactions are not common, but seem to be more common in mast cell patients than the general population.  (This is my personal observation.)  In these reactions, once the reaction is stopped with epi, you can have another anaphylactic episode of the same or worse intensity without a trigger.  This generally happens within 24 hours and is the original reason Epipens were sold in pairs.  In protracted (sometimes called multiphasic) reactions, this can continue to happen for a number of days.  I find in my personal experience that use of epi early is the best way to avoid multiphasic reactions. 
If you absolutely must take a medication that causes a serious reaction (by which I mean not a typical side effect), desensitization is usually recommended for mast cell patients as opposed to taking antihistamines with each dose.  This method really just suppresses the immediate symptoms, not the inflammatory response.  Drug reactions for mast cell patients can be serious and any reaction can escalate even when it has been mild in the past.  For patients who react to salicylates, but need to take aspirin, Dr. Castells has written an aspirin desensitization protocol that is frequently used.
Part of why people get into these cycles with rescue meds is that they often don’t understand why they are having reactions.  Mast cell patients need to keep careful inventory of their daily histamine level because things that may not cause reactions individually can cause a reaction when you have them all together.  For example, if you have a relaxing day with no stress, maybe you can eat a spinach salad.  But if you go for a walk outside in the heat, and you eat that same spinach salad, you may have a reaction.  This doesn’t just happen to mast cell patients – there are plenty of recorded instances of patients having allergic reactions to food ONLY IF THEY EXERCISED THAT SAME DAY.  This is because exercise increases histamine.  Heat increases histamine.  Eating increases histamine. Stress increases histamine.  Sex increases histamine.  So all of this histamine adds up.  So you may be able to drink a beer, or you may be able to walk two miles, but if you try to do both the same day, you may have a reaction. 
Of course, there is also an idiopathic aspect to mast cell reactions, which means that some people have symptoms for truly unexplained reasons.  However, I find these happen a whole lot less when you really track activities/histamine and try to eliminate triggers. 
Part of how I evaluate my “histamine baseline” for any particular day is by certain physical parameters that I refer to as my “mast cell dead giveaways.”  If these are present, I know I am already starting out as reactive and need to lay low and avoid histamine that day.  Allergic shiners, which look like black eyes, or dark circles under the eyes, are one for me.  Swelling in my fingers tells me I’m having some edema from mast cell degranulation.  The taste of metal in my mouth often precedes reactions.  Skin being more reactive than usual is a very clear indicator for me.  On a reactive day, squeezing my arm with my hand will make my entire arm turn red.  I take my blood pressure in the morning and if my whole arm is red or has hives when I take off the cuff, it is a clear sign to me to not take risks that day.  Any type of “cold symptoms” (cough, stuffiness, clearing of the throat, sore throat) and I have to assume infection, which contributes to mast cell activation and thus to your histamine quota. 
I have written before about how to manage mast cell reactions with medication, so please refer to that post for more details.
Keep track of your histamine inventory.  Learn the “dead giveaways” for your body so you can self check.  If you’re taking Benadryl every day for symptoms, it can often be resolved with increasing meds/ adding other meds.  Taking Benadryl every day should be avoided, especially because it causes rebound reactions that can mimic anaphylaxis symptoms. 

MCAS: Kidney, urinary and genital concerns

Like so many other places in the body, the genitourinary tract of MCAS patients can easily become inflamed.  Many patients, especially women, are treated for chronic urinary tract infections despite negative cultures.  Male MCAS patients are often diagnosed with prostatitis.   Vaginal inflammation, painful inflammation, and vulvodynia/ vulvar vestibulitis are also found frequently in mast cell patients.  (Please see previous post on vaginal pain in chronic disease.)
Mast cells are not often found in healthy renal tissue, but they are frequently present in various types of renal disease.  They are most commonly associated with tubulointerstitial nephritis associated with fibrosis and renal failure, including glomerulonephritis, diabetic nephropathy, allograft rejection, amyloid disease, polycystic kidney disease, reflux nephropathy and others.  Mast cells drive fibrosis and their presence correlates with decrease in glomerular filtration and a poor prognosis. 
MCAS patients with urinary pain often suffer from obstructive ureteral angioedema, swelling of the urethra that prevents the urine from passing through it.  Persistent lower back pain is common, with flank pain and lower abdominal quadrant pain being less common.
Fertility issues are not rare in mast cell patients.  Luteinizing hormone activates mast cells, which release histamine to stimulate ovarian contractility, ovulation and progesterone release by follicles.  Histamine is necessary for these functions and antihistamines can prevent ovulation.  Frequent miscarriage should not be readily attributed to mast cell disease.  Antiphospholipid antibodies should be considered. 
Mast cell degranulation has been implicated in testicular sclerosis via production of 15d-prostaglandin J2.  Mast cell stabilizers can help treat oligospermia significantly enough to result in pregnancy.  Decreased libido and erectile dysfunction is common in mast cell disease, including MCAS.
15-20% of women in childbearing years have endometriosis.  Endometriosis is the occurrence of endometrial tissue outside of its normal location.  In these patients, endometrial tissue is often found in the peritoneum.  These ectopic tissues are often fibrosis and cause significant inflammation. 
Mast cells are significantly increased in endometrial lesions, with 89% showing significant activation in regions that stain heavily for CRH and urocortin.  Mast cells in normal and proliferative endometrium are not activated.  Additionally, IL-1a, IL-6 and TNFa, among other inflammatory mast cell mediators, are increased in the tissue and fluids surrounding endometrial lesions.  (A detailed post on this is coming soon.)
Interstitial cystitis is often misdiagnosed as endometriosis.  In IC, urinary urgency, increased urinary frequency, suprapubic and pelvic pain and pain on intercourse are the most common symptoms.  IC is caused by increased mast cells in the bladder.  In IC patients, 146 mast cells were found over 10 high power fields; in patients with bacterial bladder infections, 97 were found; and in health controls, 51 were found.  (A detailed post on this is also coming.)

References:
Sant, Grannum R., Kempuraj , Duraisamy, Marchand , James E., Theoharides, Theoharis C.  The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis.  2007.  Urology 69 (Suppl 4A): 34-40.
Holdsworth SR, Summers SA.  Role of mast cells in progressive renal disease.  J. Am. Soc. Nephrol. 2008 Dec; 19(12):2254-2261.
Kempuraj D, Theoharides TC, et al.  Increased numbers of activated mast cells in endometrial lesions positive for corticotropin-releasing hormone and urocortin.  Am. J. Reprod. Immunol. 2004; 52:267-275.
Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.

MCAS: Anemia and deficiencies

Anemia is the most common issue affecting red blood cells in MCAS patients.  It can be macrocytic (big cells), normocytic (normal size), or microcytic.  Usually mild to moderate, but occasionally the diagnosis is mistaken for pure red cell aplasia on bone marrow examination.  When macrocytosis is predominant, BMB must be performed to rule out myelodysplastic syndrome (MDS.) 
Cobalamin deficiency is common, even when pernicious anemia is ruled out.  Copper deficiency is sometimes the cause for microcytic anemia, although in MCAS, it sometimes causes normocytic or macrocytic anemia.  This may be caused by absorption, but is also a side effect of overdose of zinc, a common ingredient in over the counter medications taken by MCAS patients to reduce symptoms. Folate deficiency is less frequently found in MCAS and is often due to hemolysis from an acquired condition like acquired chronic autoimmune hemolytic anemia, sometimes found to occur secondary to mast cell disease.  Other hemolytic conditions, like paroxysmal nocturnal hematouria, should be ruled out.
Many MCAS patients have selective iron malabsorption, which sometimes resolves with antihistamine treatment.  GI bleeds must be excluded.  Oral iron absorption tests can be done to test iron malabsorption.  A recent procedure calls for a blood sample to establish baseline plasma iron, administration of 100mg dose of oral sodium ferrous citrate, and another blood sample to test plasma iron two hours later.  Increase of less than 50 ug/dl is considered evidence of malabsorption.
Iron malabsorption can happen for several reasons in the context of MCAS.  Iron deficiency can be from MCAS immune dysfunction that leads to generation of antibodies against the acid secreting cells of the stomach.  When the concentration of stomach acid is too low (achlorhydria), the absorption of non heme dietary iron is dramatically reduced.   H2 antihistamines and PPI medications can interfere with iron absorpotion.   Hepcidin, the production of which is stimulated by mast cell mediators like IL-6 and TNFa, slows down the rate with which GI cells transfer the iron into the blood stream for use.
MCAS patients sometimes exhibit low serum iron and ferritin, but have normal MCV and RCDW, which indicates no deficiency is present.  This profile is thought to allude to correct transport of iron to the blood stream but poor utilization in the bone marrow. 

References:
Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
Kobune M, et al.  Establishment of a simple test for iron absorption from the gastrointestinal tract.  Int. J. hematol. 2011; 93:715-719.
Hitchinson C, et al. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary hemochromatosis.  Gut 2007 Sep; 56(9):1291-1295.