The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 70

84. Is the problem for mast cell patients that they can’t break down histamine properly?

  • Not exactly. Mast cells that are overly activated will make and release more histamine but the activation comes before the histamine, not the other way around. There’s no evidence that indicates that in mast cell disease there is something wrong with the way the body breaks down histamine.
  • Histamine intolerance is not a well accepted diagnosis in the general medical establishment. Histamine intolerance is when patients react to foods and activities that contain or cause the production of histamine in the body. The general thinking on why this happens is that the body doesn’t make enough enzyme to break down the histamine at a normal rate. I have not seen convincing data that histamine intolerance is in fact due to the inability of the body to break down histamine fast enough. Regardless, I know a lot of people who feel better when they take DAO supplements or each DAO rich foods. DAO (diamine oxidase) is one of the enzymes your body uses to break down histamine.
  • Please keep in mind that histamine intolerance is a distinct phenomenon from mast cell disease. In mast cell disease, the problem is that the mast cells are too activated so they release excessive histamine into the body. In histamine intolerance, the mast cells are not overly activated, and the body can’t break down histamine fast enough. This means that even if a person with histamine intolerance makes a normal amount of histamine, their body can’t break it down at a normal rate.
  • It is theoretically possible to have both mast cell disease and histamine intolerance. There’s not a reliable way to test for histamine intolerance beyond symptoms, and there aren’t really robust diagnostic criteria. Some people with suspected mast cell disease test negative despite having mast cell symptoms and responding to treatment. This means that there’s no way to definitively know right now if a trigger causes a reaction because of histamine intolerance or a mast cell reaction beyond having a prior, firm diagnosis of mast cell disease.
  • There is something I find intriguing that may be linked to histamine intolerance. I mentioned diamine oxidase (DAO) above. It is one of enzymes your body uses to break down histamine. The other enzyme your body uses for this is called histamine n-methyltransferase. When this enzyme breaks down histamine, it produces n-methylhistamine.
  • N-methylhistamine is the most common breakdown product of histamine. It is also the molecule that we test for as part of the diagnostic workup for mast cell disease. The reason we test for n-methylhistamine instead of histamine is because histamine is broken down so quickly that n-methylhistamine stays in your body much longer than histamine. We use it as a surrogate marker for histamine since it’s easier to measure.
  • I know a lot of mast cell patients who have flagrant histamine symptoms that repeatedly have normal tests for n-methylhistamine both in blood tests and in 24-hour urine tests. There are a few reasons why this could be but I have started to wonder if the reason those tests come back normal is because your body doesn’t make enough of the enzyme that breaks down histamine in this way. As I said above, there is no real evidence to support this, just something I think about sometimes.

 

For additional reading, please visit the following posts:

The Provider Primer Series: Mediator testing

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 69

83. Are there any supplements that help manage mast cell symptoms?

  • Yes.
  • Mast cell patients are often vitamin or mineral deficient.
  • Iron deficiency is extremely common. This is likely due to anemia of chronic inflammation. Basically, if your body is inflamed long enough, your body hoards the iron and stops moving it from your GI tract into your bloodstream where it can be used. Iron supplements are pretty harsh so patients don’t always tolerate oral supplements. IV iron is an option if your iron is low enough. I personally like the Lucky Iron Fish for increasing iron. It’s pretty neat.
  • Many mast cell patients are magnesium deficient. The exact cause of this is unknown. Lots of us take magnesium supplements.
  • For reasons that aren’t clear, a lot of mast cell patients are vitamin D deficient. Vitamin D acts on mast cells. There is some evidence to suggest that vitamin D can decrease mast cell activation. I personally found that effectively supplementing vitamin D has helped me a lot. A lot of symptoms I blamed on mast cell disease were actually vitamin D deficiency.
  • A number of supplements can decrease mast cell activation or block the action of mast cell mediators. There are a ton of natural mast cell stabilizers. They are sometimes used to help patients manage symptoms, especially in Traditional Chinese Medicine, which in recent years has been studied in clinical trials. Quercetin and resveratrol are commonly used by mast cell patients.
  • I take turmeric daily to reduce inflammation. Turmeric or curcumin can decrease prostaglandin production.
  • Holy Basil is a popular supplement in the mast cell community. It also decreases prostaglandin production. It can also block the histamine H2 receptor. While I often see people say that holy basil is as effective as an H2 blocker as H2 antihistamines like ranitidine or famotidine, I have never been able to find any evidence that this is true. But it does definitely have some ability to block the histamine H2 receptor.
  • Vitamin B12 deficiency sometimes occurs in mast cell patients, especially those with mast cell activation syndrome. This can have some interplay with MTHFR mutations, which can affect the form of vitamin B12 best suited to your body.
  • Vitamin C decreases the amount of histamine released by mast cells. It is recommended by some prominent mast cell researchers and many patients respond well.
  • Alpha lipoic acid is sometimes used, particularly for neurologic symptoms and neurologic pain.
  • I’m not sure if CBD oil is considered a supplement but it is widely used with excellent results. Be aware that the popular notion that marijuana derivatives do not interact with any medications is inaccurate. It especially can interact with tricyclic antidepressants to cause dangerous tachycardia.
  • Keep in mind that all supplements have the potential to interact with medications or to affect a person adversely if they have certain diseases. Exactly how much this happens is hard to pinpoint because over the counter supplements are held to a much lower standard for this type of study than FDA approved medications.
  • Always discuss any supplements you plan to try with your managing provider. Vitamins and minerals can cause toxicity and too much can cause very serious side effects and complications.
  • Do not assume that just because something is derived from nature, or because it is available without a prescription, that something is automatically safer for you than medications.
  • This is not really in my wheelhouse so I would encourage you to ask other patients what has helped them or to consult with a nutritionist.

For additional reading, please visit the following posts:

Effect of vitamin D on mast cells
Naturally occurring mast cell stabilizers: Part 1
Naturally occurring mast cell stabilizers: Part 2
Naturally occurring mast cell stabilizers: Part 3
Naturally occurring mast cell stabilizers: Part 4
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 19
MTHFR, folate metabolism and methylation

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 68

82. Why do mast cell patients react to leftover food?

  • Reacting to leftovers is arguably the strangest thing about mast cell disease. Lots of people tolerate foods that are freshly cooked but react to eating leftovers in the following days.
  • There are multiple ways that food can be broken down but I’m going to focus on how microbes do this, contributing to mast cell symptoms.
  • Microbes start breaking down food basically immediately. Any kind of food.
  • Freezing arrests microbial growth but doesn’t kill the microbes. Refrigeration slows down microbial growth but it doesn’t fully stop it. Cooking at high temperatures kills microbes.
  • Microbes break down food in several ways but the most important ones for this conversation are protein degradation and lipid (fat) degradation.
  • Proteins are composed of building blocks called amino acids. They are essentially long chains of amino acids. One of those building blocks is called histidine. When histidine is broken down, it produces histamine. This will happen when any protein is broken down, animal or plant.
  • However, animal meat contains hemoglobin, a very large protein that contains tons of histidine. Plants do not have this. This is thought to be one of the reasons why patients often do worse with meat leftovers than plant or grain based leftovers. Another reason is that some meats naturally have a high concentration of histamine to start with.
  • Lipids are found in both plants and animals but they are fundamentally different. Lipids in plants are usually oils while lipids in meats are fats. Lipids can be broken down by microbes or just by exposure to oxygen. This is what causes things to go rancid, more common in animal fats than in plant lipids. Acids and alcohols can be produced when lipids are broken down. Alcohols in particular can be triggering to mast cells.

The dying season

Things die in the fall. It is both my favorite and the worst thing about this time. The scientist in me knows that these little deaths nourish the environment so that one day all of this can be born in me. The mast cell part of me is reactive. We don’t call it Shocktober for nothing. And the human part of me is sad. It’s hard to find the same beauty in stark branches and grey skies and I know that is coming.

We are living through a season in the mast cell community, a different kind of dying season. On a weekly basis for the last two months, I have logged onto social media to discover that yet another mast cell patient has died. There are varying causes of death, including complications of anaphylaxis, organ failure, complications of treatment, and suicide. And it has now been a year since my friend, Ginger, died suddenly.

I have gotten messages from several newer patients asking if this frequency of death is common for mast cell patients. It’s not. They are understandably alarmed at the number of people in our community who have died recently. I am alarmed. Watching your friends die never gets easier. There is no amount of expectation that can blunt the pain. There is no way to prepare.

Spending time in this space feels dangerous. It is not safe to linger here.

I have never stopped being affected by the deaths of mast cell patients I only knew casually. Even if you weren’t close to someone who has died, even if the only link you have is that you both have a common rare disease, you still feel it. You are bonded to the people who understand your suffering. We are part of the same whole.

I have seen a few people express concern that over time, these people will be forgotten. They will not. I remember the name of every single mast cell patient that has died since I joined the community several years ago. I remember the shock I suffered when I learned about each of them. So will all of you.

These people are gone now. There will be no vibrant resurgence in the coming spring. But they were people with lives that touched others and living in the love those people carry is a kind of rebirth. Those people will remember the ways they are changed by having known this person. They will remember favorite things and inside jokes. They will remember goals and aspirations and hopes and faith. They will remember better days.

I want you to remember that the people who are gone can never be completely lost to us. That the things they breathed into the air linger still. That when you breathe, you are breathing them in. This world has been marked by their presence, both physically and emotionally. It has literally been changed in a way that is individual to each person. And because of that, they will never be forgotten. How could they be, when they helped to build this world?

There is a poem about death that has always resonated with me. My instructions for my funeral, hopefully many years from now, include this poem being read.

Do not stand at my grave and weep.
I am not there. I do not sleep.
I am a thousand winds that blow.
I am the diamond glints on snow.
I am the sunlight on ripened grain.
I am the gentle autumn rain.
When you awaken in the morning’s hush,
I am the swift uplifting rush
Of quiet birds in circled flight.
I am the soft stars that shine at night.
Do not stand at my grave and cry;
I am not there. I did not die.
-Mary Elizabeth Frye

Be kind to yourselves. Take care. This season will end.

Clinical trials and data for laypeople, Part 3

Initial investigation of a therapy in humans starts with a phase I clinical trial. Phase I is extremely preliminary. Its purpose is really just to verify whether the therapy can be used in humans at all. It identifies the safe range for therapy dosage and any side effects patients may experience. In phase I, a therapy is given to a very small number of people, tens of people as opposed to thousands like clinical trials in later phases.

In phase I studies, you often see many diagnoses being tested at once. For example, it is not unusual for phase I cancer trials to look at solid tumors. There could be dozens of reasons for a patient to have a cancerous solid tumor. Phase I studies are small. But when they look at several different diseases, you get an even smaller number of patients. For example, let’s say a phase I cancer trial is looking at testing New Drug X in patients with solid tumors. A total of twenty patients will participate in this study. Of those twenty patients, five may have non-small cell lung cancer and two may have colorectal cancer. So you are looking at tiny numbers of people. You are trying to prove that this therapy can be used in humans at all rather than looking at how well it works on a particular disease.

Phase II is when you start to get into the real meat of trialing a therapy. In this phase, a few hundred people are recruited. At this point, the targeted diseases are clearly defined. You don’t see tons of diagnoses being trialed like you might see in Phase I. The goals of a phase II trial are to figure out which dose is the best for treating a disease and to identify any side effects or toxicities a patient may experience from taking the therapy.

In phase II trials, trial design is less uniform. This means that not all phase II trials follow the same pattern. They are sometimes divided into two parts, called phase IIa and phase IIb. Phase IIa trials are usually dedicated to figuring out what dosage should be given to patients. In phase IIb, the studies investigate what dosage gives the best result for patients and cause the lowest level of toxicity and complications, called adverse events.

Most people are familiar with the clinical trial format where some patients get the therapy and some patients get a placebo, and neither the patients nor the investigators know who gets what until the end. This doesn’t always happen, especially in oncology and rare disease trials. For very aggressive diseases, the reason is that getting the placebo and therefore not receiving any treatment would be fatal. In such instances, some patients might get the new therapy while others would get an older therapy that is currently used for people with that disease. When a treatment plan is typically prescribed for patients with a particular diagnosis, that treatment is called the standard of care (SoC). When you read through trial data or articles about trials, you might see something like “[drug name] vs SoC”. This means that some patients get the new therapy and some get the old therapy. The patients may or may not know which therapy they are getting. This depends a lot on the disease and how the new therapy and the standard of care are administered. For example, a new therapy might be given intravenously twice a month. The standard of care could be radiation therapy once a month. For obvious reasons, patients and investigators will know what therapy they are getting. But if both treatments are given via IV twice a month, the patients may not know. The investigators may or may not know depending on the trial design.

In certain situations, a phase II trial might be designed not to compare a new therapy to standard of care, but instead to demonstrate that a therapy can be given safely at a particular dose and have the intended effect upon a disease. This might happen if there is no standard therapy available for a disease. It also happens in rare disease studies because they want to get as much data on how a therapy affects patients with the rare disease and, by nature, there aren’t a lot of patients with that rare disease. So in a study for Rare Disease Y, instead of giving 100 patients the new therapy and 100 patients the standard of care, the investigators may choose to give all 200 patients the new therapy so that they can get as much data as possible on how this drug affects patients with this rare disease.

After phase II studies, the data collected and analyzed is submitted to the regulatory body for countries where the investigators want to be able to use the drug. In the US, this is the FDA. The data is reviewed and the regulatory body will decide what the next step is to be able to use the therapy in people.

There are several possible paths from this point. The regulatory agency may decide that the data is not strong enough to show that the drug works at a particular dose safely in patients while helping their disease. They could tell the investigators to extend their phase II trial, or to design a new trial and try again. They could tell the investigators that they feel the therapy is dangerous and not eligible for use in humans. They could agree the data supports the use of the therapy in this patient population, but want to see more data on a larger population. In this instance, the next step is a phase III trial.

In scenarios where the therapy is demonstrably effective against a disease and relatively safe to use in humans, the regulatory body could also elect to approve the therapy for use immediately. In this case, no phase III trial would be needed to approve the therapy for a particular disease indication. This happens mostly in situations where there is no effective therapy currently for a disease. This has happened in rare disease trials.

Patients impacted by the Elecare Jr formulation change

Hey, MastAttackers,

I don’t want to share any details yet but I’m having a meeting next week that should hopefully move things forward with the Elecare situation.

If you have been affected by this situation, please email MastAttack with a brief description of your situation and your contact information if you would like to be contacted by the people addressing the issue.

Please use the subject line “Elecare Jr impact” so it’s easy for me to find. Use the address “mastattackquestions@gmail.com.”

Thanks!
Lisa

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 67

81. Is it true almost 20% of the population might have mast cell disease?

  • We need large scale studies in order to know for sure but this is very unlikely.
  • This figure first appeared in a paper published in 2013. This study asked mast cell patients, their relatives, and healthy control subjects to complete a questionnaire about whether or not they had symptoms of mast cell disease. 17% of the patients who were in the healthy control group reported symptoms that mast cell patients may experience. However, as we all know, you can have symptoms for a lot of reasons. Just sharing symptoms doesn’t mean anything. Also, surveys and questionnaires are known to be a bad way to collect hard data. By nature, they ask leading questions and are extremely subjective.
  • This same paper also tested for CKIT mutations in 20 mast cell patients and 20 healthy controls. The mast cell patient group included patients with MCAS, systemic mastocytosis, and cutaneous mastocytosis. The paper reported that 13/20 (65%) mast cell patients had mutations in the CKIT gene while 3/20 healthy controls (15%) had mutations in the CKIT gene. However, these mutations are not known to cause mast cell disease, or any diseases, for that matter. 20 people is a TINY number for a genetics study. You need a much larger group to really know whether or not a mutation occurs in healthy people or just people with a specific disease. We are talking hundreds to thousands of people needed in order to really know.
  • Many mastocytosis patients have a specific mutation called the CKIT D816V mutation. This mutation in mast cells only occurs when the patient has a clonal mast cell disorder like mastocytosis. People in the general population do not have the CKIT D816V without having mast cell disease.
  • Currently, the only CKIT mutations known to be associated with mast cell disease are the mutations at codon 816 of the CKIT gene. The D816V mutation is overwhelmingly the most common, but there are others that same exact spot, including D816Y, and a few others. Other mutations in the CKIT mutation are not known to be associated with mast cell disease.
  • Genes mostly tell your cells how to make proteins. The reason mutations can cause diseases is because they can change the structure of the protein that is made, affecting how it works. But not all mutations cause disease. Many mutations don’t change the proteins made by genes. This means that just having a mutation does not necessarily mean you have a disease. Mutations have to be linked to a disease by experimental work showing that people with a particular mutation have a particular disease.
  • Mutations are really very common. They occur so frequently that your cells have lots of failsafes in place specifically to work around or fix mutations. There are several ways they can do this but I’m just going to talk about one right now.
  • As I mentioned above, genes tell your cells how to make proteins. Genes are made of DNA. DNA is made of tiny building blocks called nucleotides. There are four kinds of DNA building blocks. These building blocks are grouped in bundles of three. Every one of those three DNA building block bundles tells the cell how to make a little piece of the protein. Those bundles are called codons. Then the three DNA building blocks next to that bundle tell the cell how to make another little piece of the protein, and so on. Those little pieces stick together and make the full sized protein.
  • The cell is able to make a protein by reading through this gene three pieces at a time. This is how our cells use genes to make proteins.
  • So now we know that those three DNA building blocks work together to me a tiny piece of protein. There are four kinds of DNA building blocks. What piece of protein is made is determined by which three building blocks are grouped together. There are many combinations of building blocks.
  • If one of those building blocks is mutated, it could cause the wrong protein piece to be made. So it seems that each of the three building blocks is really important to making the right protein. However, this is not the case. In fact, of those three building blocks, the last one is mostly irrelevant. If it’s mutated, it will usually still make the right protein piece. In some cases, the second one isn’t important either. The first one is the most important, but having a mutation there doesn’t always mean the protein is made wrong either.
  • So genes could potentially have up to 1/3 of its building blocks mutated without causing a problem. (I’m being very general here.) This phenomenon, in which the third DNA building block in a group can be wrong without messing up the protein is called wobble. Wobble is a built in mechanism that allows cells to make mutations sometimes without consequences.
  • That’s a lot of mutations that don’t cause problems. That’s a lot of mutations that still allow the cell to make the right protein. That’s a lot of mutations without causing symptoms or disease.
  • Your genes can withstand a lot of changes to single building blocks. When a single nucleotide is changed, it is called a single nucleotide polymorphism (snp). Most of these snps don’t cause trouble at all. The only way to know which ones cause problems is to gather up a bunch of people with these mutations and study them to see if they have diseases and, if so, which ones. So just having a mutation is not enough to know if it causes diseases without further study.

For additional reading, please visit the following posts:
Gene expression and the CKIT D816V mutation
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 2
The difference between C117+ and CKIT+
Heritable mutations in mastocytosis

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 66

80. When is chemotherapy necessary for mast cell disease?

  • For mastocytosis patients, chemotherapy is used for patients with systemic mastocytosis in whom the disease is malignant (aggressive systemic mastocytosis or mast cell leukemia) or seems to be progressing towards a cancerous form of the disease (smoldering systemic mastocytosis). There are very clear cut guidelines for this. Interferon and chemotherapy are used when a patient has smoldering mastocytosis with increasing mast cell counts; aggressive systemic mastocytosis; or mast cell leukemia, in order to kill off mast cells to slow disease progression and extend a patient’s lifespan.
  • A patient who already meets the criteria for systemic mastocytosis, who has two or more B findings, is considered to have smoldering systemic mastocytosis. SSM is a transition state between indolent SM, which has a normal lifespan, and malignant forms of mast cell disease, including ASM and MCL.
  • Having two or more of the following gets you a diagnosis of SSM: mast cell aggregates that take up 30% or more of cells in a bone marrow biopsy, and/or serum tryptase over 200 ng/mL; bone marrow with too many cells in it overall, without evidence of MDS or a myeloproliferative neoplastic disease; or organ swelling that has not yet affected organ function (swelling of the liver without ascites, spleen swelling enough that it can felt by palpation, lymph nodes swollen to 2 cm or larger).
  • Patients with SSM are watched to see if their body is making lots of mast cells quickly, or if their organs are feeling the strain of too many mast cells. One of the way they check this is to see how quickly their tryptase level increases. If their provider feels that their disease is progressing, they receive chemo or interferon to try and knock the disease down enough that they don’t reach the criteria for ASM.
  • Patients are diagnosed with ASM if they meet the criteria for SM and any of the following criteria: the body not making enough blood cells, cytopenia (absolute neutrophil count below 1000/ul, hemoglobin below 10g/dl, or platelets below 100000/ul); swelling of the liver along with free fluid in the abdomen (ascites), elevated liver enzymes, or portal hypertension; swelling of the spleen along with decreased blood cells due to damage in the spleen, excessive production of blood cells by the bone marrow to compensate, and likely resolution if the spleen is removed; malabsorption in the GI tract causing low protein in the blood (albumin) and weight loss; and severe bone dysfunction, causing a series of bone breaks and large osteolytic lesions from mastocytosis.
  • ASM patients are put on chemotherapy or interferon, usually continuously, unless there is evidence that they have killed off enough mast cells to have a less dangerous disease category.
  • Mast cell leukemia patients are on chemotherapy continuously.
  • There is no described use for chemo in cutaneous mastocytosis.
  • There are situations where patients with other disease categories (ISM, MMAS, MCAS) are put on chemo drugs to try and manage symptoms or shock episodes after all other therapies have failed. While this has been mentioned in literature, there have been no studies on it.
  • Chemo drugs should be used as a last resort. They can have significant side effects and complications that cannot always be remedied by stopping the treatment.
  • Please note that while newer, targeted chemos have become more common, they are in fact chemotherapy and carry significant risks despite being more tailored, including the potential for organ damage or failure.

For additional reading, please visit the following posts:

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Natural history of SM-AHD, MCL, MCS 

The Provider Primer Series: Mast cell activation syndrome (MCAS)

Past present

My grandmother was murdered when my father was a teenager. He spent the next several years bouncing from home to home, often staying with his friends. One of those friends became like a brother to him. Our families were very close. And when I growing up, my very best friend was that man’s daughter.

She is a year older than me and was a grade ahead in school. We lived within a mile of each other for our whole lives until she was in high school. We were together constantly, easily six or seven days a week. We had almost the same life. It is impossible to overstate how important she was to me. I loved her and wanted to be just like her.

She has struggled with addiction for more than half our lives now. Our paths diverged in high school and never crossed again. I have seen her a few times at family functions. She never looks like herself. I often see things that remind me of her or that she would like and wish I could text her to tell her. We have very different lives now. But I still miss the person she was.

I visited her today in the hospital. I had appointments in the same hospital where she is a patient. Seeing her today was a jarring experience. I wasn’t really sure what to expect. When I opened the door, she turned toward me. It was the first time in twenty years that she looked like herself. I wondered for the first time if we could ever be close again.

I stayed for a while and caught up with her before going to my appointment. My doctor and I compared my symptoms and talked about how generally improved I am. I enjoyed pretty decent health from June 2015-August 2016. “Your symptoms are more like they were after your surgery,” he commented, referring to my recovery post GI surgery in 2015. He’s right. They are.

I often wonder if the reason why I so often reach into my past to compare the present to is because I am expected to literally do this at every appointment. I’m always looking for changes since the last time I was seen. Or since the last time I felt pretty good. Or since I was diagnosed with mast cell disease. Sickness is assessed by the changes it brings about in your body, and you can only do this by dragging the past into the present.

The past can be the precarious face for the present to balance on. We can never go back. Any of us, for anything, for any reason. It is over. But sometimes it feels like I catch the past in my present. In the drudging of old wounds and deeds, pieces of our old selves and our old lives are conveyed to the now. We can fit these pieces in our growing lives. We can remake lost connections.

Our lives will never spin as freely with these old pieces, weighed down with history. But they can still be strong enough to hold you up.