The Cult of Optimism; or, Openheart

Optimism when chronically ill is like a cult. You just show up one day and decide to be optimistic. Because you are optimistic, everyone around you is also optimistic, and for a while, that makes it seem like things will be fine. Optimism is a reflex when presenting with a protracted, terrible situation. It is a defense mechanism, a sort of emotional shock that allows us to move forward.

But optimism is also a distraction, a slight of hand. It draws your attention away from the seedy underbelly of this type of thinking. When we are alone, we sit with the nameless fears we don’t share lest we shatter this illusion of positivity. You’re not supposed to talk about the bad things that could happen when you’re part of this cult.

A lot of us are worse off than we tell people, sometimes even people close to us. There are words we can’t give shape to. A sentence we type and delete.

Over.

And over.

When things started getting bad, I decided that I couldn’t control what happened, but I could control people’s expectations. I think I will be fine, but that doesn’t mean I will be. The wrong med during surgery, undercooked egg whites, a bad car accident that triggers anaphylaxis. The night is dark and full of terrors, and all that.

Believing I will survive won’t make me live longer. I can’t control that. But I can control whether or not people are surprised if something happens to me, and I don’t ever want them to be surprised. I don’t ever want anybody to say that they didn’t know how bad it was. It’s painful for me to lay it all out for them, to say the words, to share the risks. But not doing this feels like treason.

We live in a world of secondhand information, where people so often don’t remember how they know things. It makes so much of medicine and disease impersonal, removed. When someone wonders about what it’s like to live with chronic disease, I don’t want them to read emotionless facts and statistics. I want them to read this and feel my heart bleeding across the screen.

I want them to know that we’re optimistic while being scared, that being optimistic makes it easier to be alive with a disease like mine. I want them to know that optimism is a sort of bet, borrowing against a future we know might not exist. I want them to know that optimism doesn’t save lives.

A couple of days ago, a friend of a friend died as a result of chronic illness. He had many heart surgeries throughout this life, so many that he was known as Openheart Dave.   He was in this cult of optimism, too.

 

 

The truths I ignore

I had an appointment with my surgeon today. I need to have my rectum and some colon removed. It no longer has function and I essentially have a mast cell twist on diversion colitis. This has been coming for a while.

We talked about what the surgery entailed, healing time, mast cell precautions and how to suppress anaphylaxis in the days after the operation. Never once did he remind me that removing this tissue means that I will never be able to reverse my ostomy. He knew I knew. I was glad he didn’t say it.

“I would never reverse my ostomy,” I told his Chief Resident during the appointment. And that’s true. I never would. I would never want to again be in the position I was before I got it, where my life was one long GI nightmare of amotility.

I am not often surprised by my doctors, but today was one of those rare occasions. Everything that needs to be done can’t be done at once without the likelihood of complications. This means I will get the majority done during one surgery, after which I will be in the hospital for about a week, and will recover at home for 4-6 weeks. Then I will likely need a second surgery.

We set a rough date, agreed to meet again three weeks before surgery to go over everything again, and I left. I hurried down the hall past the brown wooden doors and turned quickly into a single stall bathroom. I locked the door and put my hands over my face just as the tears started, hot against my reddening cheeks.

I would never reverse my ostomy because I would not be able to function without it. I mean it every time I say it. But knowing logically that there is no reason to keep the rectum and excluded colon doesn’t make me feel less robbed. It was easy to pretend that I wouldn’t always need it, even if I only pretended with myself.  I just slammed the door on my last tiny chance at normalcy.

The reality of having an ostomy for the rest of my life is something I have avoided dealing with emotionally for quite some time.  I talk about it a lot, without embarrassment, but it sort of feels like I’m just trying to make myself feel better about this decision two years later.

There are some truths I have to ignore to survive. I have to mislead myself to be able to love the world again every morning.

 

Progression of mast cell diseases: Part 2

What is the risk of disease progression (to SSM/ASM) with ISM?

From 5-10 years after diagnosis, 1.7% (± 1.2%) showed disease progression. From 20-25 years after diagnosis, 8.4% (± 5%) showed disease progression. (Pardanini 2013)

“Overall risk of transmission to acute leukemia or ASM [from ISM] was low (<1% and 3%, respectively).” (Pardanini 2013)

In a study of 74 ISM patients, 8% progressed to SSM and 4% progressed to ASM. (Matito 2013)

 

How is ISM different from more severe categories?

“Advanced systemic mastocytosis (ASM, MCL) is marked by uncontrolled accumulation of neoplastic mast cells (MCs) in various organs with consecutive impairment of organ function, drug resistance and poor prognosis.” (Valent 2010)

In ASM and MCL, mast cells permanently disrupt the function of organs and can cause organ failure. The risk of death is independent of anaphylaxis.

“In patients with ASM, significant organopathy due to MC infiltration is found (C-findings).” (Valent, 2003)

“In contrast to ISM, patients with ASM often present without maculopapular skin lesions.” (Valent 2003)

“Mediator-associated problems occur quite frequently in ISM but are also seen in patients with advanced SM. However, in the latter group of patients, the predominant clinical problem is usually not related to mediator-associated symptoms but to the proliferation and often aggressive growth of MCs in diverse organs leading to organomegaly or organopathy, or even organ failure, also referred to as C-findings. “ (Valent 2010)

“ISM is predominantly characterized by symptoms related to mast cell degranulation/ mediator release/ and/ or allergies or anaphylaxis. In contrast, aggressive mastocytosis variants (aggressive SM, mast cell leukemia) are characterized by organ dysfunction related to mast cell infiltration.” (Pardanini 2013)

 

I have SSM, does that mean I will definitely get ASM?

“In most patients with SSM, the course remains stable over years or even decades. For these patients, we recommend to wait and watch B-findings, including the serum tryptase level, which is a reliable marker of monitoring of (S)SM even when levels are highly elevated.” (Valent 2010)

 

How is SSM different from ISM?

SSM is usually diagnosed at a later age, with an average of 64 years old.

“SSM patients also displayed significantly higher incidence of constitutional symptoms (45%), anemia (55%) and mast cell mediator levels. Average survival of SSM is 120 months. In a multivariate analysis, advanced age was the primary determinant of inferior survival and accounted for the marked difference in survival [for] SSM.” (Pardanini 2013)

“The risk of disease progression and leukemic transformation (18% in SSM) may be higher in SSM as compared with other ISM subgroups. The significantly inferior overall survival of SSM patients was largely accounted for by their older age.” (Pardanini 2013)

 

I have ASM, does that mean I will die within 41 months?

No. ASM is now recognized to have two predominant courses of disease. The first is ASM with slow progression. The second is ASM with rapid progression. Survival is dependent on a great deal of things, including mast cell burden and which organs are involved. Moreover, the 41 month mean survival did not include large patient groups treated with midostaurin, which shows more efficacy in these patients.

“Patients with ASM can show a slowly progressing or a rapid clinical course. Rapidly progressing ASM may also shift into another category of SM, ie MCL or (A)SM-AHNMD within short time.” (Valent 2003)

“An important of ASM is that the disease can present as slowly progressing ASM (similar to SSM but with C-findings) or rapidly progressing ASM. The latter may behave like MCL and can progress to frank MCL within a short time. Another important aspect is that, during progression of ASM and MCL, the KIT mutant D816V may disappear.” (Valent 2010)

“Many patients with ASM with slow progression can be kept under control for several months or even years by interferon-a or 2CdA [cladribine].” (Valent 2010)

 

What is the risk of leukemic transformation (developing MCL or AML from a pre-existing mast cell disease)?

In a cohort of 342 patients with some type of SM, 1/159 (0.6%) ISM patients, 2/31 (6.5%) ASM patients and 18/138 (13%) SM-AHNMD patients underwent leukemic transformation. (Lim 2009)

“Overall risk of transmission to acute leukemia [] was low (<1%) [].” (Pardanini 2013)

 

Is it possible for your disease to convert to a less severe category (like SSM to ISM or ASM to SSM)?

Yes. When evaluating treatment options for ASM and MCL patients, responses to treatment are classified as major response (disappearance of C findings), partial response (partial resolution of C findings), or no response. Some studies also include a minor response option.

In 2003, Peter Valent reported a 21% major response in ASM to interferon-a with or without steroids. (Valent 2003)

This link here details major and partial response rates to midostaurin in a patient group with ASM or MCL: https://ash.confex.com/ash/2012/webprogram/Paper51749.html

SSM patients with persistently refractory symptoms and/or upward trending tryptase often receive interferon-a or cladribine. I have received patient reports that it “knocked [them] back to ISM.” I have not as yet found a literature source for this phenomenon.

 

References:

Pardanini, Animesh. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) 2013; Blood: 121 (16).

Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).

Pardanini, Animesh. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. 2009; Blood: 114 (18).

Lim, Ken-Hong, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. 2009; Blood: 113 (23).

Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).

Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.

Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. 2012; Expert Review of Hematology: 5 (3): 261-274.

Valent, Peter, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. 2003; Leuk Res 27 (7): 635-41.

Hauswirth, Alexander, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. 2004; Leuk Res 28 (3): 249-257.

Progression of mast cell diseases: Part 1

Among mast cell patients, we generally assume that a designation of SM means indolent systemic mastocytosis (ISM.) However, in research papers, this term can mean ISM, SSM, ASM or MCL. Advanced SM usually means ASM or MCL. These terms generate a lot of confusion in the patient population. When reading a paper, abbreviations are usually defined on the first page or within the introduction. It is important to check on what the researchers are using the term SM for.

As an example, let’s look at this really alarming quote to someone who thinks SM means ISM:

“The life expectancy of SM patients was shorter relative to age- and sex-matched controls. As initially observed by Travis et al, survival decreased rapidly after diagnosis: to 60% at 3 years, with a subsequent slower decline to 50% at 5 years. Beyond 5 years, the slope of the survival curve was similar to that of the control population. This observation confirms that the deaths in SM patients within the first 3 (and up to 5) years after diagnosis.” (Lim 2009)

In this paper, SM meant ISM, SM-AHNMD, SSM, ASM and MCL. When you average those survival rates together, you get a sharp decline in survival for the first five years. After that, it returns to normal, because most of the ASM and MCL patients in that study died by that time.

 

I get asked A LOT about whether or not ISM is progressive. I see a lot of people describe it as progressive. In medicine, progression usually means moving from one diagnostic category to a more serious one (like ISM to SSM.) However, a lot of patients use this term to mean a worsening of symptoms or disability while staying in the same diagnostic category (like ISM with mild daily symptoms to ISM with severe daily symptoms). Those are two different things. I’m going to answer both.

 

What is the life expectancy with ISM?

It’s normal.

“Patients with ISM have a favorable prognosis. These patients may suffer from mediator-release symptoms, but do not suffer from significant organopathy caused by MC infiltration.” (Valent, 2003)

In a study of 159 patients, 2.2% ± 1.3% died within five years of diagnosis, and 11% ± 5.9% died within twenty five years of diagnosis. “The majority of deaths in this ISM cohort were unrelated to mastocytosis.” (Pardanini 2013)

In a study of 342 patients, ISM was the largest subgroup with 159 patients.  They were significantly younger at presentation (median age 49 years.) “Overall median survival was not significantly different than that of the age and gender matched control population. Advanced age was the primary determinant of inferior survival.” (Pardanini 2013)

 

Will my ISM symptoms get worse with time?

There is really no way to know. In some people, they are stable, while in others, they fluctuate. However, mediator release symptoms (degranulation symptoms) are known to be more common in ISM than ASM and MCL.

“ISM patients can be highly symptomatic; in one study, 70% reported at least some degree of functional limitation, of which 17% reported severe limitation.” (Pardanini 2013)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)

 

If my ISM symptoms get worse, does that mean I am progressing to a more severe category, like SSM, ASM or MCL?

No.

“One important aspect in this regard is that mediator-related symptoms per se are not indicative of aggressive mastocytosis unless accompanied by C-findings.” (Valent 2003)

“Moreover, organomegaly per se is not necessarily indicative of aggressive SM.” (Valent 2003)

“In fact, in a group of patients with SM, organomegaly is recorded over many years without impairment of organ function or development of C-findings.” (Valent 2003)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)

 

References:

Pardanini, Animesh. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) 2013; Blood: 121 (16).

Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).

Pardanini, Animesh. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. 2009; Blood: 114 (18).

Lim, Ken-Hong, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. 2009; Blood: 113 (23).

Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).

Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.

Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. 2012; Expert Review of Hematology: 5 (3): 261-274.

Valent, Peter, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. 2003; Leuk Res 27 (7): 635-41.

Hauswirth, Alexander, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. 2004; Leuk Res 28 (3): 249-257.

Not a cure

On New Year’s Eve 2013, I drove to Whole Foods with my color coded list of organic, low histamine foods. I spent two hours finding unfamiliar products and reading labels. I spent $300 on six bags of food.

On New Year’s Day 2014, I cooked low histamine food with my newly purchased groceries. It was the beginning of an experiment. I was going to go low histamine for 30 days in the hopes that it would calm down my mast cell reactions, autoimmune diseases and persistently debilitating pain. I had carefully planned menus and food prep schedules for all of January.

By the end of the first week, I didn’t know if I hoped this diet would help or not. Eating low histamine when work out of the home is a royal pain in the ass. You can’t eat leftovers, so you have to cook every day. I found that since I wasn’t eating bread type products, the meals were less filling, so I had to eat more often. I spent a lot of time chopping vegetables and washing dishes. And it was expensive. Very expensive.

At the end of the thirty days, I was having fewer mast cell reactions. But my GI tract was really irritated from the additional mechanical stress of eating such high residue food. While my joint and muscle pain seemed better, my GI pain was worse. I had more energy and slept better, but the GI pain and poor motility was worse. A few weeks later, I got a PICC line in a last ditch attempt to keep my GI tract moving.

I continued to eat mostly low histamine. I drink a can of soda every day. I added back in some foods that are not low histamine but which I reliably tolerate, like potatoes and limes. I cheated sometimes. But most of the time, I stuck to the low histamine diet.

The concept of curing your disease with food is not new. Fad diets have been based around this concept for many years. I think I notice it more now because “curing yourself with nutrition” talk is abundant in the places I have to peruse to find low histamine recipes. I disagree with a lot of it. And to be honest, I think a good chunk of it is really damaging and hurtful.

I believe that it is possible to feel better by changing your diet. I think dietary and lifestyle changes are really important tools in managing chronic disease. But that is not the same as curing yourself. If you have mast cell disease and you eliminate your food triggers and see a huge reduction in symptoms, you still have mast cell disease. If you eliminate your food triggers and no longer have symptoms, you still have mast cell disease. If you stop adhering to the diet, your symptoms will return. You cannot cure mast cell disease with diet (or anything else, for that matter.) You cannot. There is no cure for mast cell disease. Or for many other chronic diseases.

An article popped up in my Newsfeed a few days ago about someone who “just decided I wouldn’t be sick anymore, so I healed myself.” Stuff like this is so hard for me to read. It implies that those of us who can’t just heal themselves are deficient in mental fortitude or discipline. It implies that these people who “cured themselves” are better than us in some way, that the rest of us aren’t trying hard enough to get better.

I decided a long time I didn’t want to be sick anymore. I have tried so many things to manage my symptoms. I have tried things I am embarrassed to admit I have tried. If it were possible to cure myself of mast cell disease (and autoimmune disease and Ehlers Danlos and so on), I would have done it by now. Instead of having a magnificent recovery through healthy eating, I need to surgically remove the pieces that are damaged beyond repair and cut my losses.

I have more severe food reactions now than I used to, possibly because I am no longer desensitized to them. After an initial period of fewer reactions, they returned with a vengeance, stronger and more frequent. It’s hard to whether the source of my reactions is more internal or external. But I know with certainty that the low histamine diet did not cure me. And I know it never will.

 

 

Inconstant

The week before Christmas was crummy. I was cold and sore and my mind was fuzzy. My skin burned and my neck was hivey. I lay awake all night, my brain humming faintly. As sunlight crept into my bedroom, I burrowed deep under my covers and slept through the daylight. I woke to darkness, feeling slow and sloppy, dripping with sweat.

Two days before Christmas Eve, I drove my car to get my hair done. I didn’t feel well. I knew I would have a reaction that day, but I was hoping I could delay its onset until I finished my errands and made it home. I couldn’t. In the middle of my appointment, I called around until I found someone who could pick me up and drive my car home. I diluted and pushed IV Benadryl in the middle of a salon while rich housewives cast sideways glances.

The ride home was the setting for my personal favorite type of mast cell reaction, in which I’m uncomfortable in my own body, so exhausted that I am falling asleep, and unable to find the right words to express what I want to communicate. I collapsed into my bed and slept for hours, the heavy and dreamless sleep your body produces when it is too exhausted for imagination.

It has been less than two weeks since I wrote a post about how much better I was feeling. I couldn’t even get out of bed.

This disease has stripped away all the meaningless noise surrounding me. All my whimsical desires are gone. I don’t have any dreams left, except the very big ones. But how can I do something extraordinary when I can’t even stay awake?

In my mind, there are no limits. I can wake up every day. I can eat normal food. I can walk with stars. The limits are in my body. I strain against them, stiff and cold, like iron bars.

The Saturday after Christmas I developed sudden, mysterious and massively painful back pain. I spent most of the next week in bed. These crashes feel harder than they used to. Every time I land on my knees, the scrapes sting longer, scar deeper.

It has been two weeks since Christmas. This week I went into the office four days, a feat I haven’t achieved in almost a year. I have had a big week. I cooked meals and did work and organized medical stuff. I watched documentaries and did laundry. I started the enormous task of organizing my life for the weeks after surgery during which I will be largely unable to participate. I have slept every night this week and woken around 7am. I am tired and sore but it’s manageable.

I can’t know how I will feel in two weeks. This constant inconstancy is so hard.

Mast cell mutations: JAK2 and myeloproliferative neoplasms

Janus kinase 2 is also a tyrosine kinase like CKIT, but it is not a receptor on the outside of the cell. JAK2 is a helper protein that helps other molecules to send signals. It also affects the signaling of many clinically important molecules, like interleukin 3, interleukin 5, interleukin 5, interferon gamma, erythropoietin, thrombopoietin, growth hormone and prolactin. These molecules are involved in cell proliferation and the inflammatory response.

JAK2 mutation V617F seems to make hematopoietic cells more responsive to growth factors, causing excessive proliferation. JAK2 V617F is used as a marker for some Philadelphia negaitve myeloproliferative neoplasms (Ph- MPN), which include essential thrombocythemia (ET), an indolent disease in which too many platelets are produced; polycythemia vera (PV), in which too many red cells are produced; and myelofibrosis (MF), in which bone marrow is replaced with connective tissue that cannot make blood cells. JAK2 V617F is present in 40-50% of ET cases, 95% of PV cases, and 60% of MF cases.

In multiple studies, the frequency of JAK2 mutations in SM has ranged from 0-20% depending on the patient group. However, multiple studies have found a frequency of 4.2-5%, which is the generally accepted figure. JAK2 mutation is a strong predictor of myeloproliferative neoplasm but not necessarily of mastocytosis. However, where present in SM patients, it indicates a higher probability of developing another MPN.

In the control group of one study, 10 ISM patients without another myeloprofilerative neoplasm were negative for JAK2 mutation, and 15 MF patients without SM were negative for CKIT mutation. In the patient group, five people had both CKIT+ SM and MF. In four patients, the JAK2 V617F mutation was present. In the four patients with the JAK2 V617F mutation, it was found not only in the myelofibrosis cells (CD15+ myeloid cells), but also in the mast cells. In two of the patients, the CKIT mutation was found in the CD15+ myeloid cells of two patients. The data suggests that the JAK2 mutation may occur before the CKIT mutation in patients who have both SM and an associated hematologic disorder.

One study looked extensively at other mutations present in various types of CKIT+ systemic mastocytosis. The patient group was composed of 39 people, with 10 having ISM, 2 SSM, 5 SM-AHNMD, 15 ASM and 7 MCL. Only 2 patients out of the group were positive for JAK2 mutation. One patient had MCL, the other had SM-AHNMD. Both also had another myeloproliferative neoplasm (in the case of the SM-AHNMD patient, it was MDS.) This study found that presence of at least one other mutation in addition to CKIT D816V was associated with poorer prognosis, although presence of JAK2 V617F was not specifically identified as causing shorter lifespans.

 

References:

Schwaab, Juliana, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013, 122 (14): 2460-2466.

Soucie, Erinn, et al. Molecular basis of mast cell disease. Molecular immunology 2015, 63 (1): 55-60.

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

Sotlar, Karl, et al. Systemic mastocytosis associated with chronic idiopathic myelofibrosis. J Mol Diagn Jan 2008; 10(1): 58-66.

Heritable mutations in mastocytosis

While the most well-known mutation associated with SM is the CKIT D816V, there are numerous other mutations that can contribute to mast cell disease and presentation. The CKIT gene produces a tyrosine kinase receptor on the outside of the mast cell. Tyrosine kinases function as switches that turn certain cell functions on and off. When stem cell factor binds to the CKIT receptor, it turns on the signal for the mast cell to live longer than usual and to make more mast cells.

The D816V mutation is located in a specific part of the CKIT gene called exon 17. As many as 44% of SM patients have CKIT mutations outside of exon 17, either alone or in addition to the D816V mutation. (Please note that for the purposes of this post, SM is used to refer to SM, ASM and SM-AHNMD in keeping with the source literature.) Still, most doctors and researchers believe the D816V mutation is not heritable. This has important implications because it means many doctors also believe mast cell disease is sporadic and not heritable.

Almost 75% of MCAD (SM, MCAS, MCL) patients had at least one first degree relative with MCAD. This study, published in 2013, demonstrated that despite the non-heritable nature of the D816V mutation, mast cell disease is indeed heritable. Currently, four heritable mutations present in mast cell patients have been identified.

CKIT is often called KIT. In one family in which the mother, daughter and granddaughter have all have indolent SM, they were all found to have a deletion at position 409 in KIT (called KITdel409.) The KIT F522C mutation has been associated with ISM.   Another heritable mutation, KIT K509I, has been identified multiple times by different researchers. The first publication to identify this mutation was published in 2006. It has been found in a mother/daughter set who have ISM, and in another mother/daughter set in which the mother has ASM and the daughter has CM. This mutation was noted in a 2014 paper to be associated with well differentiated SM.

There have been reports of families in which multiple members with ISM or SM-AHNMD had the D816V mutation. Importantly, in these patients, the mutation was readily found in numerous cell types, including mast cells, CD34+ hematopoietic precursor cells, blood leukocytes, oral epithelial cells, blast cells and erythroid precursors. Despite this finding, the majority of literature continues to report the D816V mutation as not heritable.

 

References:

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

G.J. Molderings, B. Haenisch, M. Bogdanow, R. Fimmers, M.M. Nöthen. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241

Hartmann, E. Wardelmann, Y. Ma, S. Merkelbach-Bruse, L.M. Preussenr, C. Woolery, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology, 129 (2005), pp. 1042–1046

R.A. Speight, A. Nicolle, S.J. Needham, M.W. Verrill, J. Bryon, S. Panter. Rare germline mutation of KIT with imatinib-resistant multiple GI stromal tumors and mastocytosis. J Clin Oncol, 31 (2013), pp. e245–e247

de Melo Campos, J.A. Machado-Neto, A.S.S. Duarte, R. Scopim-Ribeiro, F.F. de Carvalho Barra, J.Vassallo, et al.Familial mastocytosis: identification of KIT K509I mutation and its in vitro sensitivity to imatinib, dasatinib and PK412. Blood, 122 (2013), p. 5267

L.Y. Zhang, M.L. Smith, B. Schultheis, J. Fitzgibbon, T.A. Lister, J.V. Melo, et al. A novel K5091 mutation of KIT identified in familial mastocytosis – in vitro and in vivo responsiveness to imatinib therapy. Leukemia Res, 30 (2006), pp. 373–378

E.C. Chan, Y. Bai, A.S. Kirshenbaum, E.R. Fischer, O. Simakova, G. Bandara, et al. Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype. J Allergy Clin Immunol, 134 (2014), pp. 178–187

Akin, G. Fumo, A.S. Yavuz, P.E. Lipsky, L. Neckers, D.D. Metcalfe. A novel form of mastocytosis associated with a transmembrane c- Kit mutation and response to imatinib. Blood, 103 (2004), pp. 3222–3225

Escribano, R. Nunez-Lopez, M. Jara, A. Garcia-Montero, A. Prados, C. Teodosio, et al. Indolent systemic mastocytosis with germline D816 V somatic c-kit mutation evolving to an acute myeloid leukemia. J Allery Clin Immunol, 117 (Suppl.) (2006), p. S125

Mast cells in the GI tract: How many is too many? (Part Four)

The 2009 Walker paper evaluates the mast cell count in patients with irritable bowel syndrome (both diarrhea and constipation predominant forms) and functional dyspepsia (indigestion, upper abdominal pain). This study recorded the total count of mast cells in five fields.  Additionally, two biopsies from different sections of the duodenum were taken for each patient.  I performed some calculations to convert it to mast cells/hpf to be comparable to other data presented in this series.

Mast cells were identified using an antibody to CD117, the CKIT receptor found on the surface of all mast cells. This paper found that the average mast cell count for each patient (averaged between two biopsy sites) was 33/hpf for functional dyspepsia; 45/hpf average for both types of irritable bowel syndrome; 42.7/hpf for irritable bowel syndrome with predominant diarrhea; 47.7/hpf for irritable bowel syndrome with predominant constipation.  The control group of healthy patients demonstrated an average cell count of 29.4/hpf, with a maximum cell count of 46.5 mast cells/hpf. See Table 9 for details.

Table 9: Mast cell count in stomach of patients with irritable bowel syndrome and functional dyspepsia
Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and totaled

*Note: I made some calculations to yield information that would be comparable to other research (mast cells/hpf).

 

This paper provided total cell counts in 5 hpf for two biopsies for each patient.  For example, patient A had two biopsies with one having 50 mast cells/hpf and the other having 30 mast cells/hpf. I divided each cell count by 5 to give mast cells/hpf. (50/5 = 10 for biopsy 1; 30/5 = 6 for biopsy 2).  I added these together (10+6 = 16) and divided by 2 to get the average (16/2 = 8 mast cells/hpf).

Visualization: CD117 (IHC)
Sample type Study group: Functional dyspepsia Study group: Irritable bowel syndrome (both diarrhea and constipation groups) Study group: Irritable bowel syndrome, diarrhea Study group: Irritable bowel syndrome, constipation Control group: Healthy controls
Duodenum Average Range Average Range Average Range Average Range Average Range
33 mast cells/hpf 39.2-65.4 mast cells/hpf 45 mast cells/hpf 22.2-74.8 mast cells/hpf 42.7 mast cells/hpf 22.2-65.5 mast cells/hpf 47.7 mast cells/hpf 29.7-74.8 mast cells/hpf 29.4 mast cells/hpf 15.2-46.5 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

A 2012 paper by Zare-Mirzaie evaluated colonic tissue of patients with chronic diarrhea.  Cells were detected by two methods: an antibody to tryptase, and through the use of a simple stain, toluidine blue.  The counts presented in table 10 were found using the antibody to tryptase.  Cells were counted in 10 hpf and averaged.

Table 10: Mast cell count in colon of patients with chronic diarrhea
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase, toluidine blue
Sample type Study group: Chronic diarrhea Control group A:

Healthy controls

Control group B:

No control group

Colon Average Range Average Range Average Range
21.3 ± 4.8 mast cells/hpf 17-24 mast cells/hpf 14.2 ± 3.4  mast cells/hpf 11-17 mast cells/hpf N/A N/A
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

A 2007 paper by Guilarte mentioned mast cell counts in the jejunum (small intestine) of patients with chronic diarrhea.   Cells were detected with an antibody to CD117. The cells were counted in 10 hpf and averaged.  Please note the correct use of the term “mast cell hyperplasia” rather than “mastocytosis.” See Table 11 for details.

Table 11: Mast cell count in colon of patients with diarrhea predominant irritable bowel syndrome
Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

 

Microscopy method: 400x magnification, mast cells counted in 8 hpf and averaged
Visualization: CD117
Sample type Study group: Irritable bowel syndrome, diarrhea Control group A: Healthy controls
Jejunum Average Range Average Range
34 mast cells/hpf 15.3 mast cells/hpf

 

A 2014 paper by Vivinus-Nebot assessed mast cell counts in the colon of patients with persistent GI symptoms in quiescent (inactive) inflammatory bowel diseases.   Cells were detected with an antibody to CD117. The cells were counted in 3 hpf and averaged.  The mast cell counts in this paper were uniformly low.  This implies that mast cells are involved more directly in the inflammatory GI processes, rather than specifically in diarrhea or constipation. See Table 12 for details.

Table 12: Mast cell count in colon of patients with inactive inflammatory bowel conditions
Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.
Microscopy method: 400x magnification, mast cells counted in 3 hpf and averaged
Visualization: CD117
Sample type Study group: Irritable bowel syndrome, constipation Study group: Irritable bowel syndrome, diarrhea Study group: Irritable bowel syndrome, mixed Study group: Quiescent Crohn’s disease with irritable bowel syndrome type symptoms
Colon Average Range Average Range Average Range Average Range
12 mast cells/hpf 9-16 mast cells/hpf 12 mast cells/hpf 10-15 mast cells/hpf 12 mast cells/hpf 10-17 mast cells/hpf 12 mast cells/hpf

 

6-16 mast cells/hpf
Distribution not stated. Distribution not stated. Distribution not stated. Distribution not stated.
Sample type Study group: Quiescent Crohn’s disease Study group: Quiescent ulcerative colitis with irritable bowel syndrome type symptoms Study group: Quiescent ulcerative colitis Study group: Healthy controls
Colon Average Range Average Range Average Range Average Range
12 mast cells/hpf 4-16 mast cells/hpf 12 mast cells/hpf 9-15 mast cells/hpf 10 mast cells/hpf 5-15 mast cells/hpf 6 mast cells/hpf 2-9 mast cells/hpf
Distribution not stated. Distribution not stated. Distribution not stated. Distribution not stated.

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

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Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

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Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.