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mast cell disease

These little indignities

My back started hurting in the middle of the night on Saturday. I didn’t lift anything heavy or exercise or slip. I was just lying in bed. I walked around and tried to stretch but I could barely walk. I took round the clock pain meds for the next two days and overthought why it hurt. I thought about the likelihood of pyelonephritis, splenic distress, compression fractures. It was not my best work. (If you’re looking to not sleep when you have sudden onset back pain that started at night, google “night time back pain.” You’ll be all set.)

Pain is a huge trigger for me. My doctors recognize this and agree that managing my pain is very important to avoiding anaphylaxis. Honestly, it is probably the lynchpin to this whole shebang. When I can maintain a workable baseline, I get stable pretty quickly. So when laying on a heating pad is giving me 6/10 pain and walking is more like a stabby 8/10, it bodes poorly for my no epi streak.

I called my PCP’s office first thing on Monday morning. It was easy, since I had been up all night in pain. I told her who I was, that I had a rare blood disorder and that being in pain could cause me to go into shock. The receptionist was dismissive.

“You can see another doctor,” she started before I cut her off.

“I’m not going to spend an hour explaining my disease to someone who doesn’t know me,” I said, wincing. I am all for educating, but not when I am in huge pain and borderline mast cell attacking.

“Well, then it looks like you’ll be waiting until 3:30, because that’s the only time he has room. It’s the same rules for everybody,” she said, her voice half an octave higher than it was when she answered the phone.

“Tell him it is me and that I am in a lot of pain. Just tell him. Don’t schedule anything. Just tell him I am in a lot of pain.”

“Okay, I’ll tell him when he comes in at 8:30,” she answered.

At 8:32, I got a phone call. “He says to come in right away, can you be here at 9:45?” she asked, a little breathless. “Yup,” I said, warm with victory.

It was a small win, but it mattered a lot. “It only took you ten years to find a good doctor,” my mother commented as she drove me a few towns over to his office. It’s true. I have lost count of the doctors who called me crazy, accused me of Munchausen’s, thought I was drug seeking. Also numbering into the dozens are providers who refused to acknowledge or effectively treat my rare disease. The amount of health care losses I have accumulated over my lifetime is staggering.

I take Zofran three times a day, every day, in order to not constantly throw up. I have a prior authorization for the quantity. This summer, my doctor wrote a prescription for 270 tablets per 90 days. The mail order pharmacy filled it correctly and shipped it out. In October, I submitted a refill request. When the order arrived, the prescription had been altered to 27 tablets with 40 refills because “that many ondansetron is obviously an error,” the pharmacy supervisor told me. After three phone calls, they eventually agreed it wasn’t an error. I had to call three more times to get them to agree to change the prescription back and send me the 243 tablets I was owed. Over 15 hours of my life to correct a mistake.

Last week, I went to pick up a prescription at my local pharmacy. I worked for this pharmacy chain in the pharmacy for almost ten years. They told me I didn’t have a prescription to pick up. I gave them information on when it was called in, when I was notified it had been received, and suggested that it had been returned to stock. Two of the staff behind the counter reiterated that there was no prescription, that I was wrong, that it had never even been refill requested so I was just confused. When I explained again that I couldn’t go without this medication, the pharmacist snapped, “You don’t need to tell me that!” before turning away. Awesome.

“You think it was returned to stock?” the third staff member asked. “Yea, I’m pretty sure,” I said, pretty irritated after ten minutes of arguing. “I’ll take a look,” he offered. I sat down and waited.

Thirty minutes later, one of the other staff members called my name. The prescription was ready. “You found it and you didn’t even tell me?” I asked, incredulous. I had now wasted an hour in the store. She rung me out without looking at me, obviously offended by the audacity in asking them to find a prescription for a medication I cannot go without. She shoved the prescription across the counter and walked away. Two months ago, this same pharmacy dispensed me a prescription for 1mg prednisone with both 1mg and 5mg prednisone in the same bottle. I got a phone call with a bored apology.

These little offenses constitute a huge portion of my yearly interactions with the healthcare industry. For every one person who is interested in actually rendering me decent care, there are many more who think my case is too complicated to be worth the time. For every pleasant interaction, there are five incidents in which I am treated rudely. For every ten mistakes that are made, one may actually hurt me. I lose hours and hours to begging people to correct mistakes they made so that I can get my medication or medical supplies or appropriate treatment. The effect this stress has on my health is significant.

Patients are disadvantaged in their relationships with health care providers. The system is not set up to work for us. It can be a struggle to get medication and appointments and records and care. We stand to lose much and they stand to lose nothing. If they treat us poorly, there is very little chance of real consequences. If they make incorrect notes (THIS HAPPENS ALL THE TIME), they are unlikely to fix them even when you point out the errors. If they label you as crazy, all of your providers will see that note for years to come. It is frustrating and insulting and sometimes humiliating. We just have to take it.

But the alternative is to not get care, and that’s not an option for people like me. I have no choice but to regularly submit to these situations which literally sicken me because they have something I need. It’s scary going to doctors you don’t know, and going to unfamiliar emergency departments, and switching insurance, but the only way out is through.

I saw my doctor on Monday morning. We ruled out all the scary stuff and he wrote me some muscle relaxers. We discussed a pain med schedule and he sent me on my way. “Call me if you any problems,” he said on the way out. It was a good reminder that sometimes it’s worth the trouble. We may have to fight for treatment in the system, but outside of it, there’s no hope at all.

We can do this.  Stand up and fight.

 

Winter, the dark.

I am not a summer girl. I never have been. Years before the heat made me sick, I would look forward to fall and the smell of fallen leaves and the way they crunched underfoot.

Summer was never for me. It was just too bright.

September and October are my favorite time of the year. I am a Boston girl and I love everything about New England autumn. I love the way the light looks icier, bluer coming through the trees. I love the feel of chilly air on my cheeks as I walk through the city. I love opening the window at night and falling asleep to the scent of frost. I love Halloween. I love watching scary movies every night while I write in my journal. I love the way bare tree branches silhouette against the swollen harvest moon.

I love all these things; but I still feel the coming dark.

I get very introspective in the fall. For the rest of the year, I look forward, move forward, but in the fall, it seems I can only think back. Festive October gives way to cold November nights, to bleak Decembers, where the horizon swallows the sun before 4:30 and everything tastes like regret. I write a lot about life, about my past. I wonder about the moments that my life hinged upon, about who I would be if I had turned differently.

I like my life. It’s just that the darkness makes the past seem so large. It unlocks in me this door to melancholy and it unfurls around me, splendid and devastating.

Depression is an organic process of mast cell disease. It is part of the disease, not a side effect of living with a chronic illness. I know that these racing thoughts and weariness with the world are from masto. I know that I’m not really hopeless on the bad days, but it doesn’t matter. By the time December is half over, I don’t even think I can tell the difference.

Tomorrow is the shortest day of the year. Then the light will return.

There is beauty in the darkness. It’s just so cold here.

Food allergy series: Mast cell food reactions and the low histamine diet

When I started my posts on food allergies, I listed out the causes of food hypersensitivity. Notably absent from this list was mast cell disease. Even among detailed publications on mast cell disease, food reactions are often unmentioned (though potentially subsequent anaphylaxis is usually included.) Unfortunately, food reactions in mast cell disease are still not well understood. Even among experts, the nature and importance of food reactions in overall disease is the subject of much disagreement. Some contend that food reactions are a manifestation of general mast cell reactivity, while some think the foods specifically are sources of reactions. Following this logic, some experts believe in the validity of observing a low histamine diet while others do not.

So please keep in mind that the science behind the low histamine diet is not well accepted or even well defined. I’m going to give you my general comments on the low histamine diet, how I eat and how it has worked for me. It is my personal opinion.

A low histamine diet is one which eliminates or minimizes histamine in the food consumed. I have talked at great length about histamine so I’m not going to reiterate that here. What I will say is that exogenous histamine has been shown to induce mast cell degranulation, which means that histamine from an outside source can cause degranulation. It makes sense to me as a scientist that eating histamine rich foods will cause mast cell degranulation. It especially makes sense because the most commonly problematic food substances for mast cell patients, like alcohol, vinegar and aged cheeses, are major degranulators. I have never been able to tolerate alcohol, so it made sense to me that it was because of degranulation. Again, I prefer to lean on good studies, but in the absence of that, I will accept my own experience living in this body.

Last winter, I was in a lot of pain and generally having a sucky time of life. One of the changes I discussed with my doctors was the low histamine diet. It was in the “this can’t hurt” category. I had put off elimination dieting for a long time due to time and financial constraints, but it seemed like the appropriate time to do it had arrived.

One of the first things that became aware to me was that there is no universally agreed upon low histamine diet. There are lots of websites that discuss it and lay out diet guidelines and none of them are in complete agreement. So I just picked the one that seemed the most reasonable to me and went from there. As a mast cell patient, any diet you pick will require customization.

The diet I picked was the Histamine and Tyramine Restricted Diet by Janice Joneja. It can be found on the Mastocytosis Society Canada page.   I like this diet a lot. I do not know Dr. Joneja personally, but when I read diet/nutrition articles by her, I find them to be based in science. They meet my common sense rule. I’m going to summarize the general guidelines of the diet below along with my comments.

Key guidelines for a low histamine diet:

  • Anything fermented should be avoided. Fermentation produces histamine as a side product. Some are only sensitive to yeast fermented products while some find that fermentation from any organism is triggering.
  • No preservatives and no dyes.
  • No leftovers and nothing overly ripe. This is one of the harder parts of this diet, but I find it very important. Fresh or frozen products seem okay. I have mixed success with thawing frozen meat, but lots of people do it successfully. The key is to not cook something, put it in the fridge and eat it three days later.
  • No canned products.
  • No pickled products.

Milk and milk products: Avoid fermented products, like cheeses of all kinds, kefir, yogurt, sour cream, cottage cheese and cream cheese. A fair amount of milk products are allowed. Milk (cow, goat, coconut) is allowed, as are cheese type products that are made without fermentation (mascarpone, ricotta, panir.) Some versions of this diet allow mozzarella cheese and I find that it is safe for me. Ice cream is allowed if it doesn’t contain other disallowed ingredients. Cream products are okay, too.

Grains, breads: Yeast is the component most likely to be triggering in these products. Many people choose to restrict gluten due to their individual biologic reactions to it. Gluten is not specifically restricted on this diet, but I can tell you that it basically ends up being excluded anyway because gluten containing products usually also contain yeast. Pure, unbleached flour or grain of any kind is allowed. Products that use baking powder for leavening are allowed, like biscuits, soda bread, scones and muffins. Crackers without yeast are allowed, as are cereals if they don’t contain excluded ingredients, including artificial dyes or preservatives. I have a very difficult time finding low histamine baked products that are premade, so I generally make my own. It is surprisingly easy to make good tasting baked products with safe ingredients at home.

Vegetables: The list of vegetables that aren’t allowed feels really disjointed and counterintuitive. There is not much to do beyond committing it to memory. Not allowed: potato, avocado, green beans, eggplant, pumpkin, sauerkraut, spinach, sweet potato, tomato, any overly ripe vegetable. I personally can eat potato and sweet potato without any problem and do pretty much every day. Removing tomato was a revelation for me. It’s hard to live around because we use it for so much, but I really feel so much better. I will sometimes have a little for immediately get a stuffy nose and headache. All other vegetables are allowed. Any green that is NOT spinach is allowed. I eat a huge amount of squash, which is a really versatile ingredient. I get lots of different types from supermarkets or farmers’ markets and I make soups, purees, baked squash, squash lasagna, squash steaks, and a million other things. I can always tolerate it. This diet has also pushed me to get familiar with less common ingredients, like taro root, breadfruit and lotus root.

Fruits: Again, the list of fruits that aren’t allowed doesn’t provide any obvious unifying factor to quickly identify something as safe or not. Not allowed: citrus fruits, including lemon and lime; berries, including cranberries, blueberries, blackberries, gooseberries, loganberries, raspberries, strawberries; stone fruits, including apricots, cherries, nectarines, peaches, plums, prunes; bananas, grapes, currants, dates, papayas, pineapples, raisins. Allowed fruits: melons (keep in mind that some people may have an oral allergy syndrome reaction to melons), apple, pear, fig, kiwi, mango, passion fruit, rhubarb, starfruit (not safe for those with impaired kidney function), longans, lychees. I eat a lot of fruit, especially apples and mangoes.

Meat, fish and eggs: All shellfish are prohibited. They naturally have a huge amount of histamine. No processed meats (cold cuts.) Eggs are allowed if they are allowed. Raw egg white is a HUGE histamine liberator. Fish is allowed ONLY IF IT IS FRESHLY CAUGHT, GUTTED AND COOKED. There are differing opinions on what this means but several sources estimate it must be cooked in less than 30 minutes from catching. So unless you are or are married to a fisherman/woman, I think this is unlikely to happen. Any meat should be fresh or thawed from frozen. Leftover meat should not be consumed.

Legumes: Soy is the big culprit here because it’s in everything and is not allowed. Also not allowed: green peas, sugar or sweet peas, red beans and tofu. Everything else is allowed, including lima beans, chickpeas (I eat a ton of chickpeas), pinto beans, white beans, navy beans, black eyed peas, black beans, lentils (I also eat a ton of lentils), split peas, peanuts, and real peanut butter.

Nuts and seeds: All okay except for walnuts and pecans.

Oils: All okay except for oils that contain preservatives like BHA or BHT.

Spices: No anise, cinnamon, clove, curry, cayenne, nutmeg. Everything else is okay.

Sweeteners: No unpasteurized honey, chocolate, cocoa beans, cocoa. Most others are fine, including pasteurized honey, sugar (of really any kind), maple syrup, pure jams and jellies. This diet says plain, artificial sweeteners are okay. They are definitely not for me. One of the very first things I was told by mast cell specialist was not to use artificial sweeteners. So you can judge for yourself.

Drinks: A lot of drinks are restricted, including all teas. Most fruit juices and drinks have some type of unapproved ingredient. Milk, pure juices, water, mineral water and coffee are the allowed drinks. I also sometimes make “muddled” drinks where I crush some safe fruit with a mortar and pestle, make a simple syrup, and then put the muddled fruit in some soda water with some simple syrup.

Miscellaneous: Not allowed: Yeasts, yeast extract, all vinegars, flavored gelatin. Allowed: plain gelatin, cream of tartar, baking soda and baking powder.

The diet recommends a strict four week adherence to determine if it works. I think this is pretty accurate. I did it with no cheating for five weeks. It helped a lot. I slept better, I wasn’t swollen all the time and I was less nauseous. But there were some downsides. The first is that it is a royal pain in the ass if you work because you really have to cook every day. The restrictions on meat meant that I had meat about once every 2-3 weeks. Not everything freezes well so making a lot ahead of time isn’t always a good idea.

Finding recipes can be hard because the fact that they are labelled low histamine does not mean that they ARE low histamine. Please be very careful with that. I also find that some sources for low histamine recipes seem to assume a high level of economic freedom in food purchasing, as well as access to expensive and difficult to find ingredients. I can shop at Whole Foods, which has a knowledgeable staff and a good stock of ingredients for diets like these. There were several components I still cannot find. I also spent literally $1000 at Whole Foods for the five weeks when I initially did this diet.

One unexpected result of this diet was that it resensitized me to foods that I had become desensitized to. So foods that used to bother me a little now cause a severe reaction (sometimes anaphylactic, requiring epinephrine.) I understand that the reason for this is because these foods always caused reactions but I was effectively “used” to them so I didn’t notice. Regardless of the reason, my life is a lot more difficult foodwise than it used to be. I can “cheat” with some foods with medications but the reactions are still bad. I don’t always know how I feel about my choice to do the low histamine diet in my particular situation, but the fact is that since I did, I now am forced to observe a version of it, probably for life.

So that’s my run down on the low histamine diet.

 

 

Self evident

For hundreds of years, prominent practitioners of medicine believed that miasma was responsible for disease. This so called “bad air” was thought to arise from rotting flesh and to contaminate its surroundings. This idea was widely believed and identified convergently in various traditions, from the ayurvedics in India to the plague doctors in Europe. As epidemics decimated the population, artists drew black robed spectors with scaly feet and sickles – miasma, the very incarnation of Death.

In 1546, Girolamo Fracastoro described a theory in which epidemics are caused by seeds that transmit disease through either direct contact or indirectly. In the coming centuries, various scientists proved links between disease and organisms –Louis Pasteur, who connected puerperal fever and Vibrio; Ignaz Semmelweis, who realized that women died disproportionately in delivery when attended by physicians responding directly from autopsies; and Robert Koch, who at long last solidified germ theory as the basis for infectious disease. He proved that organisms cause disease. Like all good science in years down the road, this fact seems self evident.

In 1972, Stanley Prusiner met a patient with Creutzfeldt Jakob Disease (CJD.) A devastating neurologic disease, it literally causes the brain to develop large porosities and to look like a sponge on autopsy. CJD is just one of several known spongiform encephalopathies, which include Kuru, a disease transmitted by cannibalism in Papua New Guinea; scrapie, which affects sheep; and the most famous, Bovine Spongiform Encephalopathy, better known as Mad Cow Disease. These diseases are universally fatal. All of them were thought to be due to a “slow virus” that had never been isolated.

Ten years after his fateful encounter with a CJD patient, Prusiner published a paper in Science that identified the cause of these diseases: not an organism, not a bacterium or a virus, but a protein. His experiments described how this protein, found in abundance in the brain, when misshapen, could somehow induce the rest of their proteins to refold themselves the wrong way. His data described not an infection by a living thing, but a completely novel disease causing process. It involved no DNA or RNA, it involved no replication or gene expression. It just involved one molecule with the wrong shape causing everything around it to fall apart.

The ensuing fallout from Prusiner’s publication was nasty. Science, real science, is cutthroat. It is competition for funding. It is spreading rumors. It is discrediting. In 1986, an article in Discover accused Prusiner of seeking fame over science – the very worst slur in research. They said he didn’t care about the damage he was doing to the dogma of biology, that he didn’t even care whether or not he was right.

That’s the thing though – sometimes it doesn’t matter if you want to be right, if you are. In 1997, Stanley Prusiner was awarded the Nobel Prize for his identification of prions (infectious proteins) as the causative agents of these transmissible spongiform encephalopathies. And while prions still have detractors, for microbiologists of my generation, we find prion theory to be self evident.

A hard fact about mast cell disease is that the science behind it is being unspooled right now. That is the trouble with learning things in real time – the pull of history is still so strong for many doctors and scientists. They are loath to unlearn the things they know, to look at the data, to change their perspectives.

In the last few days, I have spoken with several people with masto kids who have either had their children removed from their care or who are at great risk of this occurring. And there is another family that I suspect is right now living this nightmare of losing their child because their rare disease is poorly understood and under recognized.

Medical professionals turning aside solid science in favor of accusations and ego is not just a failing in the system. It is life ruining, traumatizing, unthinkable. It is a tragedy.

I am not a religious person. But I kneel faithfully at the altar of science. When the monsters howl at the door, science protects us, comforts us, promises us that these horrors cannot go on without end. People say that there isn’t a time limit on important discoveries, but of course there is. If it doesn’t arrive in time to help, it is utterly devoid of meaning.

It is not enough that our bodies try to kill us, that the treatments cannot give us our lives back, that current diagnostic methods are inaccurate. We are told over and over again that we are not as sick as we say, or that we are not sick at all, or that parents project these diseases onto their children, that our suffering is the result of anxiety and overactive imaginations. They take our dignity, our livelihoods, our children.

Saying we are crazy, that we are liars and deceivers, does not make us not sick. It just makes us sick with little chance of effective treatment.

I don’t know how much longer we can live like this, how many more weeks like this I can stand. I don’t know how much longer I can wait for doctors to realize that mast cell activation disorders are real. I don’t know how much longer I can wait for them to agree that these diseases, that our suffering, is self evident.

 

Future realities

I love data. I love scores, charts, trends. I collect information, categorize things, make lists. I love data because it’s not malleable, not mutable based upon your current reality. Data does not lie.

I keep track of my life in a little red binder. I record various data in color coded ink. When I woke up and what symptoms I had when I did. What time I took my medication. What I ate. What I thought about. How much pain medication I needed, if I had IV meds, my IV fluid volume. I draw my yoga routines in soft violet curves, map the routes I took to walk the dogs. And at the very bottom of each page, a hand drawn table, double lines under the header, my most important tool in tracking my health.

There are three columns: symptoms, score, notes. I might skimp on other details (on terrible days, I sometimes just write NOOOOOOOOOOOOOOOOO across the page), but I fill out this table every night. I have been doing it for almost three years. Every night in bed, I score my symptoms: nausea, vomiting, GI motility, flushing, hives, headache, GI pain, bone pain, other pain, energy level, sleep. I record how bad they were out of 10. Indelible. Immutable.

Last month, my doctor called me to discuss options for dealing with my ongoing GI issues. They all sounded really stupid. I told him they were sounded stupid. But I’m out of options that don’t sound stupid so I tried the one that seemed least likely to harm me while probably doing nothing. It has helped a shocking amount. I sleep at night. I’m not exhausted all day. I don’t have to brush vomit acid out of my mouth several times a day. I can do yoga regularly. I can cook. It makes my bone pain worse for some reason, but frankly, I don’t care. The global improvement in my symptom profile is that dramatic.

I started a liquid/ soft solid diet in October. I mostly eat pureed vegetables and protein drinks. I drink a lot of bone broth. It is boring and annoying and sometimes upsetting, but it is definitely working. I have been adjusting medication for months, trying to find the balance between coverage and not sleeping for 20 hours at a time. With the gut rest afforded by my easily digestible diet and the addition of this new medication, I seem to have found a working combination.

I saw my doctor on Tuesday. For once, we shared good news. My biopsies were mostly clean. My bloodwork is better. I will need surgery to have the (has no function, hurts and bleeds all the time) end of my GI tract removed, but this is not surprising. I am doing better. A lot better.

The thing about reality is that whatever one you are living right now feels like it has been your reality forever. When you have a bad month, you can’t remember the last time you felt good. When you feel hopeless, you can’t remember life without smothering darkness. Your current experience colors all your other experiences. It makes your present situation seem bigger and heavier and more permanent.

A year ago, I was living the darkest, coldest part of my life. Every day was a struggle. Every minute was a struggle. This was a year of telling myself every minute, “You can do this. You can do this.” Even when I was sure I couldn’t. Even when I felt hollow, my very life force long since sapped away.

But now I can line up the pages of my binder and flip through them. Like an old cartoon, a story appears: the numbers in my tables go down, and I get better. Data doesn’t lie.

I don’t know if this will last. I don’t know how hard it will be to recover from surgery. But it doesn’t matter. Right now I am packing to go to Colorado this week and going to Disney for New Year’s Eve and studying for exams and making big plans that I hope to share soon.

A year ago, I could never have believed that I would feel like this now. I am healing my body. I am recovering my life.

There is no limit to the things we can do. Reality is temporary. There is always a future. There is always the possibility of new realities.

Food allergy series: Food related allergic disorders

The term “food allergy” is generally used by medical professionals to refer to IgE mediated allergic responses. However, it is used in a broader sense by patients who have similar conditions because the term is more likely to be understood. The truth is that there are several types of allergic disorders provoked by foods. They are all listed below and will be expounded upon in the coming days.

IgE antibodies mediate the following types of reactions. All of them have immediate onset of symptoms following interaction with the antigen.

  • Oral allergy syndrome. This presentation is usually mild. It causes itching and mild swelling in the mouth, progressing into the throat about 7% of the time, with less than 2% of cases progressing to anaphylaxis. OAS occurs due to sensitization to pollens. These pollens have specific shapes that are recognized by the IgE molecules; certain raw fruits and vegetables may shapes that are close enough to be recognized by the same IgE molecules. This is known as crossreactivity. Cooking the food changes the shapes seen by the IgE molecules and is therefore cooked forms are usually safe. In birch pollen sensitive people, apples, peaches, pears and carrots can cause crossreaction; in ragweed sensitive people, melons can be problematic. This is usually diagnosed by skin testing with the raw fruits/ vegetables. OAS can persist and be problematic during the season when the offending pollens are most prevalent.
  • Asthma irritation, including rhinitis. This can be caused by inhaling the food protein. It is most common in infants and children with the exception of work exposures in adults, like Baker’s asthma. This most commonly occurs with the eight major allergens: egg, milk, wheat, soy, peanut, tree nuts, fish and shellfish. Skin testing and serum IgE measurement can be used for diagnosis.
  • Urticaria and angioedema. This occurs when an offending food is ingested or contacts the skin (contact urticaria.) Food exposures cause 20% of acute urticaria cases and 2% of chronic urticaria cases. It is much more common in children and usually occurs after exposure to the eight major allergens. Skin testing and serum IgE measurement can be used for diagnosis.
  • GI hypersensitivity.Immediate onset vomiting can occur in response to the major food allergens. Skin testing and serum IgE measurement can be used for diagnosis.
  • Food associated, exercise induced anaphylaxis. This occurs following ingestion of food after recent completion of exercise. It is thought that exercise affects the way the GI tract absorbs and digests allergens. This most commonly affects adults, with wheat, shellfish and celery being the most common foods to provoke this reaction. Skin testing, serum IgE measurement, component testing and exercise testing can be used for diagnosis.
  • Delayed food-induced anaphylaxis to meat. This occurs several hours after ingesting the meat. It occurs when the body generates antibodies to carbohydrate a-Gal, which can be induced by tick bites. Beef, pork and lamb are known to cause reactions in a-Gal sensitive people. Testing should include serum IgE to a-Gal.
  • Anaphylaxis. I have addressed this in detail before. It can occur in response to any food, but the eight major allergens are most common. It results in massive mast cell degranulation, leading to cardiovascular collapse.

Some allergic responses to food are due to both IgE mediated reactions and delayed cell-mediated reactions.

  • Atopic dermatitis. In children with AD, about 35% of moderate/severe rashes are due to food reactions. This is thought to be due to food reactive T cells locating to the skin. It is most common in infants and least common in adults. All major allergens can be causative, but egg and milk are the most common. AD is usually self limiting. Skin testing and serum IgE measurement can be used for diagnosis.
  • Eosinophilic GI disease (EGID.) Eosinophils are inflammatory cells that share a lot of functions and behaviors with mast cells. Like mast cell disease, eosinophilic disease can affect a variety of organs, most commonly the GI tract. Symptoms are widely variable and related to level of inflammation and infiltration. It often causes difficult or painful swallowing, weight loss, obstruction and edema. EGID is related to the activity of several mediators, include IL-5, eotaxin, which causes eosinophils to home to various inflamed locations. Much like mast cell disease, it can occur in response to a wide array of foods. Elimination diets are first line treatments for EGID. Endoscopy, kin testing and serum IgE measurement can be used for diagnosis, but elimination diets are often used empirically for diagnosis.

Some allergic type responses to food are not due to IgE antibodies.

  • Food protein induced enterocolitis syndrome (FPIES.) Usually found in infants, repeat exposure to certain proteins causes chronic vomiting, diarrhea, low energy and poor growth. Exposure again following a period of abstinence from offending substance can cause vomiting, diarrhea and 15% drop in blood pressure. These reactions occur about two hours after ingestion. Cow’s milk, soy, rice and oat are the most frequently reported sources, but many others have been recorded. In FPIES children, their cells are more responsive to TNF-a and less responsive to TGF-b. FPIES usually resolves with age, but can be difficult to diagnose due to skin testing and serum IgE testing usually being negative.
  • Food protein induced allergic proctocolitis. This causes mucuosy, bloody stools as a result of eosinophilic response in infants. This occurs in response to milk through breast feeding and resolves when the substance is removed from the mother’s diet.
  • Heiner syndrome. This rare condition is marked by pulmonary infiltration, upper respiratory symptoms, iron deficiency anemia and failure to thrive. It occurs in infants and is triggered specifically by milk. It is thought that there may be a milk specific IgG reaction.
  • Celiac disease. This autoimmune disease causes malabsorption and enteropathy. It is a response to gliadin, a gluten protein in wheat and other grains. It can cause bone abnormalities, IgA deficiency, dermatitis herpetiformis and a variety of other complications. It can present at any age and is lifelong. Blood testing during food challenges, GI biopsies, and testing for HLA DQ2 and DQ8.

Cell mediated reactions are not due to IgE antibodies.

  • Allergic contact dermatitis. This type of eczema occurs in response to metals in foods. This occurs mainly in adults. It is diagnosed by atopy patch testing.

Mast cell reactions to food are related to inappropriate degranulation which has not been fully characterized. Mast cell food reactions will be discussed more completely in an upcoming post.

 

Reference:

Sicherer, Scott, Sampson, Hugh. Food allergy: Epidemiology, pathogenesis, diagnosis and treatment. J Allergy Clin Immunol 2014, 133 (2): 291-307.

 

The other side of the sky

I am the type of person who experiences memory through music. I cannot always remember the vividness of color or feeling when revisiting in my mind, but one verse immerses me in the rich details of sense memories. Three right chords and I am reliving it.

A few days ago, as I was stepping into the shower, Wagon Wheel by Old Crow Medicine Show came on. Immediately, I was in Portland, Oregon last July. I was going for a walk well past midnight, my Epipens in my dress pocket, clanging against my thigh with each step. The air was still warm, humid, but not cloying; just sort of close in the way summer sometimes is. I signed along to the song in ASL as I walked, an old habit from when I was learning.

Driving across the bridge into Portland was the culmination of surviving years of surgeries and shocks and lost pieces of myself. I felt amazing there, filled with this lightness, but also sad around the edges. This disease is so unpredictable. I loved it there so much and I don’t know if I’ll ever get there again.

Last week, I scheduled an appointment with my colorectal surgeon for January to discuss the removal of the end of my GI tract. It no longer has any function and causes me a fair amount of grief. That same day, I booked my flights to Colorado. I was not feeling great emotionally because frankly I’m tired of surgeries and procedures but physically I have been feeling much better. I am sleeping at night and not vomiting every day and don’t feel like a zombie all the time. Anything better than normal feels like such an improvement.

In the next three months, I am planning to visit Florida, Minnesota, California and potentially Hong Kong. It’s a lot of travel for anyone, let alone someone like me. That’s the thing about feeling better – it gives you this artificial bravery to do things you normally wouldn’t. It makes you feel like you can do things you know you can’t. What if I could, though? What if I could do all things I think I can?

I had one of those cries in the shower that night, when Wagon Wheel came on, the kind with wrenching, full body sobs. It had been building all week. Every morning that week I woke up feeling okay and all day I waited for it to get worse. I was afraid of how bad it would feel when this good went away. I was afraid I would remember that I can’t do all these things I want to do, and I was afraid that I would be right.

When I have a really good day, I tell people that I feel like I could fly, like I could touch the sky if I wanted to. Feeling good after not for so long does strange things to your mind. It makes it feel like you can bend the limits of your reality.

Standing in the water, I had an image in my mind of me touching the sky only to have it break apart under my hand. And on the other side of the sky, there was this other place, with no limits, and it terrified me.

When I feel good, part of me is afraid of feeling bad again. But I think there is also a part that is afraid for another reason. I think part of me has no idea how to function outside of these confines my disease has built for me. I think if I was healthy tomorrow, I wouldn’t even remember how to live anymore.

 

MTHFR, folate metabolism and methylation

MTHFR (methylenetetrahydrofolate reductase) is an enzyme involved in folate metabolism. It is rate limiting, which means that if there is not enough, your body cannot metabolize enough folate; if there is too much, it metabolizes too much. How much folate your body is able to metabolize is directly related to how much MTHFR you have in your body.   Some folate broken down by your body is used to methylate DNA. There has been much conflicting evidence, but it seems that low folate in the body is associated with less DNA methylation overall, which may be associated with cancer (Crider, 2012.)

A single nucleotide polymorphism (SNP) is a change in DNA sequence in which one nucleotide (a DNA building block) is changed. Importantly, SNPs are common. In fact, they are so common that the way your body codes its DNA allows for SNPs to not change gene expression in many cases. This is called wobble. Three DNA building blocks in a row make one amino acid, which is used to build proteins that do things in the body. However, in many cases, the third building block can be any building block and it will still make the same amino acid. Please consider this. SNPs are so common that your cells know that in many cases, 1 in every 3 DNA building blocks can be anything and it won’t change a thing.

SNPs have become the topic of increased interest, both by medical and scientific professions and by lay people. It is certainly true that some SNPs play a role in development and progression of diseases. MTHFR has been found to have up to 24 reported SNPs, with two being of particular interest. These are C677T and A1298C.

The normal (or “wildtype”) form of MTHFR has a cytosine (C) nucleotide where people with the C677T mutation have a thymine nucleotide. If you have two copies of the regular gene, you are 677CC and homozygous for the regular form of the gene (the allele.) If you are 677CT, you have one copy of the allele with the SNP. If you are 677TT, you have two copies of the allele with the SNP. About 10% of North Americans are 677TT, meaning they have two copies of the mutated allele. It is most common in Hispanics and those of Mediterranean descent, next most common in Caucasians and least common in African Americans (Schneider, 1998.)

Being homozygous for 677TT can cause a mild MTHFR deficiency because that this form of the enzyme is generally less stable, which means it breaks down faster than usual. People with this profile are also more likely to develop mild hyperhomocysteinemia, an elevation of homocysteine in the blood. Homocysteine is consumed in the metabolism of folate, and because there is less MTHFR with the 677TT mutation, the homocysteine is not all getting used. It is also elevated in cases of B6, B12 and folic acid deficiency.

Increased homocysteine has been studied for its possible relationship to health issues, including increased clotting, strokes, schizophrenia and osteoporosis. Despite multiple studies (to be honest, quite a lot of studies), the results are really non-uniform. Because it was linked earlier to cardiovascular disease, multiple studies investigated the benefits of lowering homocysteine. In diabetic nephropathy patients, treating to lower homocysteine actually doubled cardiovascular events including heart attack and stroke, some leading to death, as well as decreased renal function (House, 2010.) But another study found lowering homocysteine decreased the risk of stroke by as much as 25% (Lonn, 2006.)

The effects of the C677T SNP have been most well studied in regards to development of cancers. Folic acid is a key metabolite in the development and proliferation of cells, so deficiency can be limiting to cell division. 677TT patients who are not folate deficient are actually 50% less likely to develop colorectal cancer or colorectal adenoma (Chen, 1999.) 677TT patients who are folate deficient have at least the same risk as 677CC patients and potentially more risk (Slattery, 1999.) 677TT patients are over four times less likely to develop acute lymphocytic leukemia. They have the same risk of developing acute myeloid leukemia (Skibola, 1999.) Some studies found them to have increased risk of cervical neoplasia, breast cancer, endometrial cancer and gastric cancer, but all of these studies were done on small populations (Xia, 2014.)

The other MTHFR SNP that gets a lot of attention is A1298C. At position 1298 of the MTHFR gene, the wildtype allele has adenine. In some people, it is substituted for cytosine. Wildtype is homozygous for adenine there and they are called 1298AA. If you have one copy of the SNP, you are 1298AC. If you have two copies, you are 1298CC. The A1298C has much less effect on the stability of the MTHFR protein than the C677T mutation. It is not known to cause elevation of homocysteine levels. There has been a lot of controversy over whether this mutation can cause a deficiency of BH4, tetrahydrobiopterin. BH4 is important in formation of neurotransmitters and nitric oxide, as well as consuming ammonia. Low levels of BH4 have been tied to phenylketonuria and trials with BH4 supplementation have seen encouraging results (Michals-Matalon, 2007.)

In the last six months or so, I have read about fifty scientific papers on MTHFR or related topics. I did this because I originally planned an MTHFR post for last summer. I didn’t do a post because the data is a mess. You cannot ascertain much of use from the peer reviewed literature on the C677T and A1298C mutations – and not for lack of effort. These mutations have been very well studied.

MTHFR mutations and methylation are talked about a lot in the mast cell community. Many people believe that having an MTHFR mutation severely impacts folate metabolism, which in turn means there is not enough methylation, and this dysregulation causes overexpression of genes causing disease. I have searched thoroughly for a link. Really thoroughly. I cannot find any link that is not the idea of one person and researched by that one person, usually outside of peer reviewed settings. I cannot find any link that is not described in detail by a person who does not stand to gain financially from patients who share their beliefs. I am not saying that MTHFR is definitely not linked to mast cell disease. I’m saying I can’t find any proof that it is. I can’t even find anything that SUGGESTS that it is. Might people with these mutations feel better with appropriate folic acid supplementation? Probably. Is that the same thing as causing mast cell disease? Certainly not. It is certainly not the same thing.

I think personal stories hold a lot of power. If your personal story is that your mast cell disease is significantly better controlled by addressing your MTHFR mutation, then I think that is fantastic. I think it is entirely possible that this is the case for many. But I do not believe it causes mast cell disease. And I think everyone would feel better with appropriate levels of folate, as it is an important player in many vital reactions.

 

References:

Schneider JA, Rees DC, Liu YT, Clegg JB (May 1998). “Worldwide distribution of a common methylenetetrahydrofolate reductase mutation”. Am. J. Hum. Genet. 62 (5): 1258–60

M L Slattery, et al. Methylenetetrahydrofolate reductase, diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev., 8 (1999), PP 560S-564S.

House, AA; Eliasziw, M; Cattran, DC; Churchill, DN; Oliver, MJ; Fine, A; Dresser, GK; Spence, JD (Apr 28, 2010). “Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.”. JAMA: the Journal of the American Medical Association 303 (16): 1603–9.

Lonn, E; Yusuf, S; Arnold, MJ; Sheridan, P; Pogue, J; Micks, M; McQueen, MJ; Probstfield, J; Fodor, G; Held, C; Genest J, Jr; Heart Outcomes Prevention Evaluation (HOPE) 2, Investigators (Apr 13, 2006). “Homocysteine lowering with folic acid and B vitamins in vascular disease.”. The New England Journal of Medicine 354 (15): 1567–77

Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G’ (October 1999). “Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults”. Proc. Natl. Acad. Sci. U.S.A. 96 (22): 12810–5.

Kim, Y I, et al. Methylenetetrahydrofolate reductase polymorphisms, folate and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutr Rev 58 (2000), pp 205-209.

Crider, Krista, et al. Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role. Adv Nutr January 2012 Adv Nutr vol. 3: 21-38, 2012

Xia, Lei-Zhou, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility. World J Gastroenterol. Aug 28, 2014; 20(32): 11429–11438.

J Chen, et al. MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among US men and women: an example of gene–environment interactions in colorectal tumorigenesis. J. Nutr., 129 (1999), pp. 560S–564S

Lesser known mast cell mediators (Part 4)

Interleukin-1a (IL-1a) is largely responsible for inflammation, fever and sepsis. It activates TNF-a and the work very closely together. Their cofunctions include PGE2 synthesis, nitric oxide production, insulin resistance and IL-8 and chemokine production.

Interleukin-1b (IL-1b) has been implicated in several autoinflammatory syndromes. It is also important in cell proliferation, differentiation and apoptosis. Its induction of COX2 cytokine in the nervous system contributes to inflammatory pain hypersensitivity.

Interleukin-2 (IL-2) is crucial in prevention of autoimmune disease by regulating T cell differentiation. It is also thought to be involved in itchiness and psoriasis. IL-2 is used in the treatment of cancers.

Interleukin 3 (IL-3) drives the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells. If IL-7 is also present, they can work synergistically to trigger differentiation into lymphoid progenitor cells. IL-3 induces proliferation of all myeloid cells (including mast cells) along with other cytokines like IL-6. It supports growth and differentiation of T cells from bone marrow when an immune response is triggered.

Interleukin 4 (IL-4) changes naïve T cells to T helper cells, which secrete chemicals to drive actions of other immune cells. T helper cells then secrete additional IL-4 to perpetuate the cycle. IL-4 participates in the airway inflammation seen in allergic asthma.

Interleukin 5 (IL-5) encourages growth of B cells and antibody secretion as well as eosinophil activation. It is heavily involved in allergic diseases, particularly those in which eosinophils are notably increased. Mepolizumab is a monoclonal antibody against IL-5 that can reduce excessive eosinophils.

Interleukin 6 (IL-6) mediates fever and the acute phase inflammatory response. It is secreted to stimulate bone resorption and inhibitors of IL-6 are used to treat osteoporosis (including estrogen.) It inhibits TNF-a and IL-1. Unusually, it also has anti-inflammatory behaviors, particularly during exercise in the muscle.

Interleukin 9 (IL-9) increases cell proliferation and impedes apoptosis, cell death, of hematopoietic cells. It is particularly important in asthma and bronchial hyperresponsiveness.

Interleukin 10 (IL-10) is an anti-inflammatory molecule involved in regulating the JAK-STAT pathway. It counteracts many of the inflammatory effects of mast cells, often by interfering with production of substances like interferons and TNF-a.   Exercise increases levels of this molecule.

Interleukin 13 (IL-13) is critical in initiation of airway disease. It induces matrix metalloproteinases to act. IL-13 can also induce IgE release from B cells. It is effectively a link between allergic inflammatory cells and the non-immune cells they interact with. Excessive , IL-13 causes airway hyperresponsiveness, goblet cell metaplasia and oversecretion of mucus.

 

I think I might have mast cell disease: FAQ

What kinds of symptoms do mast cell patients have?

Mast cell disease can cause a variety of symptoms. Each person has their own unique constellation of complaints, and they can vary from day to day. Mast cell patients often have allergic type reactions to many things. They may have had anaphylaxis in the past, but that is not always the case.

What kind of doctor should I see if I think I have mast cell disease?

Due to the fact that mast cell disease can affect multiple body systems, it is managed by doctors of multiple disciplines. Immunologists, dermatologists, gastroenterologists and hematologists/ oncologists all may treat mast cell disease. It really depends who is familiar with mast cell disease in your areas. Immunologists are often the first stop for patients investigating mast cell disease.

Will any doctor know about mast cell disease?

No. Mast cell disease is uncommon. Many doctors are only aware of the types associated with pathologic rashes (cutaneous mastocytosis) or proliferation of mast cells in the bone marrow (systemic mastocytosis.)

How do I get determine if I have mast cell disease?

Labs for diagnosing mast cell disease include serum tryptase (a blood test), n-methylhistamine (24 hour urine test) and D2/F2a prostaglandin (24 hour urine test.) These tests are time sensitive for many patients and have special handling in most labs. Depending on these results, a bone marrow biopsy may be needed.

Can I have mast cell disease if my tryptase is normal?

Yes. 15% of patients with systemic mastocytosis have normal tryptase levels, and the majority of MCAS patients have normal tryptase levels.

How is mast cell disease treated?

Treatment generally focuses on the symptoms. The most common treatments include antihistamines, leukotriene inhibitors and mast cell stabilizers.

Will I feel better with treatment?

Most people feel better with treatment than without, but how much each person recovers is individual. Lifestyle modifications and medications can help many people live a full life.

Is mast cell disease curable?

No. Patients may have a remission from symptoms, but they will always have mast cell disease.