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Lisa Klimas

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

Horizon

The last couple of months have been really stressful. Several of my work projects are all requiring a lot of attention right now. I am trying to iron out some details around MastAttack and make plans for the future. I live in the grey bleakness of New England in the midst of a record breaking winter. I am having some setbacks regarding GI function and pain.

And of course, I am having surgery soon. The amount of feelings I have about this surgery is surprising given the fact that I have always expected to have it. I don’t know. I guess it just seemed further off. The horizon seems so far away until you’re standing on the edge of the world, about to fall off.

Bowel surgery when you have mast cell disease is a complicated affair. I have to get buy in from all the relevant specialists and they all have to agree on a plan. I have to schedule surgery when everyone is in town and not taking vacation in the near future. I have to arrange care (nursing and otherwise) for weeks after I leave the hospital. I have to finish up several work things before they operate. I want to get some things lined up for MastAttack before I go.

My surgery was scheduled for April 28. I saw my surgeon this week to go over everything. He is not convinced that removing all of my colon is the best move. I am going to repeat some motility testing. Specialized testing generally takes weeks to get scheduled. Which would literally give us the results days before my scheduled surgery date, and that’s cutting it a little close for me.

I scheduled all my testing, then called my surgeon’s secretary. I rescheduled my surgery for mid-May. I am frustrated that there is still disagreement so close to my surgery date, but I understand why. We can’t just look and see what happened to the last twenty people like me who had their colons removed. There just isn’t anyone like me.

Part of why this whole production has been stressful is because I saw this coming a mile away. Needing my colon removed is not a surprise. We discussed removing more of my colon when I had my surgery in 2013 (I still have about 70% of my colon).   We weighed the pros and cons then, so I feel like having a similar conversation two years later shouldn’t generate so many questions. But things change, and my body has changed, and I have changed, as a person. What I want now is not the same as two years ago.

I thought pushing back the surgery would make me mad, but it really didn’t. It was a relief. I immediately felt calmer. It gives me time to make decisions without pressure. It gives me time to take some time for myself and focus on the things I care about.

If the amount of messages I have received are any indication, the weight of my life in recent months has been apparent to my readers. You guys are fantastic. You are so sweet and kind and respectful of my time and my feelings. I really feel so privileged to be part of this thing we are all doing together.

It has not escaped notice that MastAttack is turning into a much larger undertaking than I could ever have anticipated. I think some people are worried that I write these posts and answer questions out of a sense of obligation. A few weeks ago, I took a week off from the blog. I didn’t research or write anything about mast cell disease.

But at the end of the week, all I wanted to do was write posts about mast cells and diabetes. Not because I felt like people would be upset if I didn’t. Because I wanted to write it in case it was helpful. And because I like doing this.

In the last few months, this amazing thing has been happening. I am getting questions from people that are very nuanced, that show a really good understanding of the biology involved. Some of these questions are coming from people who have progressed a long way in their understanding of this disease. They are questioning me and bringing up findings from papers I haven’t read or correcting me when I get sloppy with the details. It is so cool. We are getting somewhere. This is getting to be bigger than me. And that was always the point.

I’m going to tell you guys a secret. I don’t want to be doing this in ten years. I don’t want to be writing articles or posts or reading literature constantly. In ten years, I want all this information to be available in a concise, easy to digest form for anyone to use. I want so many people to know everything that I know that I become obsolete. It’s starting, and you’re all part of that.

Along those lines, it’s time for me to get some help with all of this. I’m taking some people up on offers to help out, and will be asking for help with specific tasks in the upcoming months. If you think you might want to help, feel free to message me on FB or send me an email. There will be more details in future posts.

As for me, I’m feeling decidedly less stressed than I have in a while. All of my work stuff will either get done or it won’t, and all of my blog stuff will either get done or it won’t.   I’ll have surgery and I think it will help. And if it doesn’t, it doesn’t. The risk of ending up with a permanent ileostomy is scary, but not trying to remove a huge source of inflammation and live without an ostomy is scarier. You can’t be afraid to try.

In the meantime, I’m taking some time to relax before this next stage of my life begins. I’m going to Florida to visit a dear friend (and Disney!) later this week. The week I was supposed to have surgery, I will be going to California to visit Team Addie, my mastsister Addison and her family. And deciding to do those things felt warm and peaceful. It is exactly the right medicine for this weariness.

So I guess what I’m trying to say is that I appreciate all of your support. And I appreciate all of you individually more than you know. Every time I see someone jump in with the right answer or a message of support, I am honored to be part of this. And I’m so thankful and touched by your messages of concern and support. It’s nice to have people to catch you once in a while.

Sometimes things are hard, but everything’s gonna be okay. Okay, or better. It’s like my guarantee.

 

Allergic to infections: How bacteria, viruses and fungi activate mast cells

I am often asked about whether an infection, even a mild cold, can cause worsening mast cell symptoms.  The answer is yes.  Viral, fungal and bacterial infections can all cause mast cell activation, and patients with prior activated mast cells are especially susceptible.  This is why it is so important for mast cell patients to avoid contagious illness as much as possible.

Several cell types in the human body have Toll-like receptors (TLRs) on their cell surfaces. These receptors bind many types of molecules that indicate presence of infection. These molecules are called pathogen-associated molecular patterns (PAMPs) and they share similar shapes that identify them as being released by infecting organisms. When these PAMPs are bound by TLRs on cell surfaces, it sends signals for the cells to mount an immune response.

The expression of TLRs on mast cells has been well studied using both mouse (murine) and human mast cells. TLR1, 2, 3, 4, 5, 6, 7, 9 and 10 have been identified on mast cells by at least one study. Some of these TLRs were only detected by finding related mRNA. (When cells express a gene to make a protein like a TLR, the DNA gene is copied into mRNA, which tells the cell how to make the TLR.) Since only the mRNA and not the TLR was directly identified, these TLRs require more research to be fully characterized.

TLR2 is one of the most well studied and understood of toll-like receptors found on mast cell surfaces. TLR2 is also known as CD282. Substances that bind to TLR2 include many molecules released by bacteria and fungi. Several types of peptidoglycans and found in bacterial cell membranes bind TLR2. In particular, lipoteichoic acid is a potent activator of TLR2. This molecule is found on the surfaces of gram-positive bacteria, like Staphylococcus spp. (Staph, MRSA) and Streptococcus spp. (Strep). Other bacteria that are known to activate TLR2 include Neisseria meningitides, Haemophilus influenzae, and Borrelia burgdorferi, among others. Mycobacteria are also activating to TLR2. Zymosan is found in cell membranes of yeast and binds TLR2. Aspergillus fumigatus (fungi) and several viruses, including Herpes simplex, Varicella zoster, Cytomegalovirus and measles, activate TLR2 responses. Heat shock protein 70 (HSP 70) is released by cells in the body when they are under certain types of stress, and this can activate TLR2.

When TLR2 is bound, mast cells produce and release several types of molecules that are not prestored in granules. The molecules released depend on which protein has bound TLR2. These molecules include IL-1b, which causes inflammatory pain hypersensitivity; IL-5, which activates eosinophils; leukotriene B4, which forms reactive oxygen species and participates in inflammation; leukotriene C4, which causes slow contraction of smooth muscle, including in the airway; GM-CSF (Granulocyte macrophage colony-stimulating factor), a growth factor for white blood cells; TNF, which has many inflammatory effects; RANTES, which brings other white cells to the site of inflammation; and others. TLR2 activation is responsible for the worsening of asthma symptoms in the presence of bacterial infection.

Multiple studies reported that stimulation of TLR2 with peptidoglycan (a constituent of gram positive bacterial cell membranes) induced degranulation. Stimulation with peptidoglycan induced histamine release as well as cytokine release in a 2003 study (Varadaradjalou 2003). Another study found that peptidoglycan did not cause statistically significant degranulation, but zymosan (a fungal product) and Pam3Cys (a synthetic molecule that acts like LPS, another component of bacterial membranes) did induce significant degranulation (McCurdy 2003). Other studies have not been able to replicate these results.

There is also evidence that stimulation of TLR2 can change the behavior of mast cells. When mast cells are grown in the presence of bacterial cell membrane products, they make different amounts of different proteins. Another study demonstrated that two bacterial cell membrane products downregulated the amount of FceRI (the IgE receptor) on the surface of mast cells, so after two days, mast cells were less responsive to stimulation by IgE molecules. This was partially due to the effects of TLR2 (Yoshioka 2007).

However, mast cells that are sensitized react more strongly to TLR2 activation with LPS (Medina-Tamayo 2011). This effect seems to be reliant on prior binding of IgE. Other very technical studies have investigated the effect of antigen (such as bacterial, viral or fungal products) on the interplay between the IgE receptor and TLR receptors.   While most of this work has been done in mouse cells, several investigators have shown that activation of TLR receptors and the IgE receptor causes enhanced release of cytokines but not degranulation. It is thought that the exaggerated response to IgE receptor and TLR2 stimulation can cause the exacerbation of allergic type conditions during active infection. (Qiao 2006)

 

References:

Hilary Sandig and Silvia Bulfone-Paus. TLR signaling in mast cells: common and unique features. Front Immunol. 2012; 3: 185.

Abraham S. N, St John A. L. (2010). Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10440–452.

Dietrich N., Rohde M., Geffers R., Kroger A., Hauser H., Weiss S., Gekara N. O. (2010). Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proc. Natl. Acad. Sci. U.S.A.1078748–8753

Gilfillan A. M., Tkaczyk C. (2006). Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol.6218–230.

Fehrenbach K., Port F., Grochowy G., Kalis C., Bessler W., Galanos C., Krystal G., Freudenberg M., Huber M. (2007). Stimulation of mast cells via FcvarepsilonR1 and TLR2: the type of ligand determines the outcome. Mol. Immunol. 442087–2094.

McCurdy,J.D., Olynych,T.J., Maher, L. H.,and Marshall, J.S.(2003). Cutting edge: distinct Toll-like receptor2 activators selectively induce different classes of mediator production from human mast cells. J. Immunol. 170, 1625–1629.

Medina-Tamayo, J., Ibarra-Sanchez, A., Padilla-Trejo,A., and Gonzalez- Espinosa, C. (2011). IgE-dependent sensitization increases responsiveness to LPS but does not modify development of endotoxin tolerance in mast cells. Inflamm. Res. 60, 19–27.

Qiao,H., Andrade,M.V., Lisboa,F. A., Morgan,K., and Beaven, M. A. (2006).FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107, 610–618.

Yoshioka,M., Fukuishi,N., Iriguchi,S., Ohsaki, K., Yamanobe,H., Inukai, A., Kurihara,D., Imajo,N., Yasui, Y., Matsui, N., Tsujita, T., Ishii, A., Seya,T., Takahama,M., and Akagi, M. (2007). Lipoteichoicacid down- regulates FcepsilonRI expressionon human mast cells through Toll-like receptor2. J. Allergy Clin. Immunol. 120, 452–461.

Varadaradjalou, S., Feger, F., Thieblemont, N., Hamouda, N.B., Pleau, J. M., Dy,M., and Arock, M. (2003). Toll-likereceptor2 (TLR2)and TLR4 differentially activate human mast cells. Eur. J. Immunol. 33, 899–906.

Diabetes, steroids and hypoglycemia

Following alloxan induction of diabetes, rats overexpress glucocorticoids. This in turn depletes the mast cell populations in the skin, lungs and intestines. Glucocorticoids interfere with production and expression of tissue cytokines and stem cell factor, a growth factor for mast cells.

Several experiments have definitively proven that these steroids are responsible for downregulating mast cell growth and activity. Treating diabetic rats with the steroid receptor blocker RU486 or removing adrenal glands on both sides of the animal causes an increase in intestinal mast cell numbers and IgE formation.

The mechanism by which steroids confer these effects is thought to involve insulin. Glucocorticoids inhibit secretion of insulin in the pancreas. In turn, insulin release decreases systemic glucocorticoids. Additionally, insulin also activates mast cell signaling pathways. In the presence of insulin, antigen induced mast cell degranulation and survival is upregulated. In diabetic rats, administration of insulin recruits mast cells and increases response to antigen. Insulin treatment can reverse the reductions in mast cell populations, histamine production and IgE release seen following alloxan administration.

Increased activity of the HPA axis is often seen in type I and II diabetics, resulting in elevated cortisol. One study showed that appropriate activity can be restored with insulin treatment. This is achieved by a complex mechanism in which expression of glucocorticoid receptor mRNA is elevated in the pituitary, facilitating glucocorticoids to suppress expression of ACTH release.

 

Can hypoglycemia cause mast cell degranulation?

Yes. Activation of histamine 1 and 2 receptors as a result of insulin or hypoglycemia causes release of ACTH. Hypoglycemia (low blood sugar, which can also be induced after administration of insulin) normally increases ACTH levels in the blood. However, higher than normal histamine levels in the blood can interfere with the action of ACTH, which would normally address hypoglycemia via production of glucocorticoids. One study found that this effect can be mostly ameliorated by pretreating with antihistamines, though I suspect in mast cell patients, this may not achieve the full response seen in non-mast cell patients.

 

Can anaphylaxis cause hypoglycemia?

Yes. In instances of severe stress (emotional or physical), corticotropin-releasing hormone (CRH), neurotensin and substance P are released. Among other things, CRH can induce mast cell degranulation (of note, CRH does not directly induce histamine release via degranulation). CRH also causes increased expression of the IgE receptor on mast cells, which increases the likelihood of being stimulated and thus degranulation (this may cause histamine release). In tandem, neurotensin and substance P increases the expression of the CRHR-1 receptor for CRH on mast cells so that they are more sensitive to CRH. Likewise, neurotensin and substance P act on mast cells via receptors to induce degranulation (this causes histamine release). As a result of this degranulation, histamine and other mediators are present to inhibit the action of ACTH, which would otherwise increase blood sugar (via the production of cortisol, epinephrine, and norepinephrine).

 

References:

Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.

Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.

Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.

Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673

Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2

Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.

Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.

Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.

Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.

S.C. Cavalher-Machado, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.

Off the reservation

I am not sure how this is possible, but I have actually never interacted with Brynn Duncan. For those who don’t know, she is one of our young adult mast cell patients. She is very photogenic and seems lovely. She writes a blog about her life and her health struggles. Recently, she has been the subject of some articles on various sites (Buzzfeed, among them) and so I have read about her a lot in the last few weeks.

Today, the American Academy of Allergy, Asthma & Immunology (AAAAI) posted a link to an article in Cosmo about Brynn. (Link here: http://bit.ly/1FvAlUN) In the way that often happens when you have a relatively new, complex medical condition, people began speculating in the comments. Some had questions about her diagnosis (specifically, the criteria used, and whether she met them).

One of the better aspects of rare disease communities is that when the internet feels like doubting the disabling and life altering nature of your condition, there are plenty of people to have your back. The mast cell community showed up in the comments and made their reality known. Mast cell patients know what it is to be doubted, and to suffer for years because of that doubt. They felt that people were doubting Brynn and they reacted in the way they felt best supported her.

Also, please keep in mind that sick people who share their stories for awareness are people. They are people with boundaries and rights to privacy. It is very possible that all of the salient details are not captured in public media.

But there is another layer here that needs to be addressed. And that is this: what exactly is MCAS, and how do you know if you have it? And if you test negative, do you still have it? And that is a conversation that we need to have both inside the community, for patients, and outside the community, for providers to be able to treat mast cell patients effectively.

If you go through the peer reviewed literature, there are multiple sets of diagnostic criteria for MCAS. This is not helpful, but is pretty common for newer diagnoses. Specifically, it is not unusual for clinical entities that don’t have WHO or ICD diagnostic criteria. Clinicians group people together based upon sets of clinical findings, and sometimes lab findings, and uses those as markers for this previously undescribed entity. Doctors and scientists disagree with each other a lot, and so you develop multiple schools of thought on what constitutes X diagnosis. So you potentially multiple distinct groups of patients with the same name attached to their diagnosis. It is very confusing, and can really complicate things when you try to identify exactly what commonalities unify these people.

One of the commentors mentioned that he felt a well-known doctor in the mast cell community used very lax criteria to diagnose MCAS, and in particular, did not meet the criteria published in JACI (J Allergy Clin Immunol). For clarity when referencing my post on differing MCAS criteria, the 2010 Akin and the 2012 Akin, Valent, et al, Consensus proposal, were published in JACI. The Afrin and Molderings 2011 was published in J Hematol Oncol. Here is a comparison of published diagnostic criteria for MCAS:

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, and Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.

 Cem Akin, MD, PhD, Peter Valent, MD, Dean D. Metcalfe, MD. Mast cell activation syndrome: Proposed diagnostic criteria. Volume 126, Issue 6, December 2010, Pages 1099–1104.e4 Peter Valent, Cem Akin, Michel Arock, Knut Brockow, Joseph H. Butterfield,

Melody C. Carter, Mariana Castells, Luis Escribano, Karin Hartmann, Philip Lieberman, Boguslaw Nedoszytko, Alberto Orfao, Lawrence B. Schwartz, Karl Sotlar,

Wolfgang R. Sperr, Massimo Triggiani, Rudolf Valenta, Hans-Peter Horny,

Dean D. Metcalfe. 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;157:215–225.
MCAD (umbrella term including both MCAS and SM) diagnosed if both major criteria, or one major criterion and one minor criterion, are present; following bone marrow biopsy, diagnosis is narrowed down to either SM or MCAS MCAS diagnosed if all criteria are met MCAS diagnosed if all criteria are met

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

Minor Criteria
Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
Mast cells in bone marrow express CD2 and/or CD25
Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved
Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

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

 

Additionally, there are differences of opinion on whether or not having a primary mast cell disease (mastocytosis, etc) disqualifies you from having MCAS. Most agree that MCAS can be secondary to another condition, including a number of autoimmune conditions. However, whether allergic type symptoms accompanying systemic mastocytosis, for example, qualifies as MCAS is still not agreed upon. Some feel that these symptoms are inherently part of the SM diagnosis, and that MCAS is a diagnosis of exclusion. Others feel SM refers to a proliferative condition, whereas MCAS refers to the inappropriate allergic response. It is a mess for patients, caregivers, researchers, doctors familiar with the condition and doctors who aren’t.

Compounding this issue is the fact that the test most doctors are likely to be familiar with (tryptase) often yields results in normal range. Sometimes, patients experiencing flagrant anaphylaxis under the banner of MCAS will not even demonstrate the 2ng/ml + 2% above baseline that some experts consider indicative of degranulation. Tryptase, like all other mediator tests used to diagnose MCAS, is time sensitive. But sometimes one normal tryptase is enough for doctors to dismiss MCAS as a possible diagnosis (for the record, about 15% of SM patients also have normal tryptase levels).

But then how do you know it’s MCAS and not something else? Therein lies the crux. I think for patients who are experiencing unmistakable anaphylaxis resolved by epinephrine, it is a smaller jump of logic to land on MCAS. But what about so many mast cell patients with non-specific symptoms and negative test results? Do they all have MCAS?

The answer is that we don’t know, and furthermore, that it depends heavily on how you define it. Many doctors use response to typical mast cell medications (antihistamines, stabilizers) as proof of MCAS. But mast cells are involved in so many types of inflammation that treating mast cell degranulation is likely to help with a number of other conditions as well. If the patient is improving, I think most doctors are inclined to continue treatment while still looking for other possible causes. But what if the patient doesn’t improve? What if they get worse?

Diagnoses of exclusion can be dangerous in that many times it is eventually proven wrong. Treating for the wrong disease can be disastrous – both in the potential adverse effects and in the potential to mask the true diagnosis indefinitely. I understand the reluctance to operate under an unusual diagnosis with no empirical proof that it is the right one.

However, there is also a long precedent in medicine in treating “like” diseases with treatments defined for its look alike condition. For example, treating someone who “looks” like they have lupus, as regards symptoms or borderline laboratory findings, with lupus medications is not unusual. And I think that this needs to be considered. Because at the end of the day, MCAS patients are sick. These are people who often have severe, life threatening anaphylactic episodes and daily symptoms that affect their ability to function in the world. Making an educated guess and proceeding cautiously is a well established practice in medicine.

All biomarkers were once unknown. Medicine, and science, are living entities that evolve over time. Eventually causes for diseases are identified and tests developed, and then better tests. This is just another example of not being able to detect well something we haven’t known for very long we needed to look for.

In spite of these difficulties, I think it’s important for clinicians not to lose sight of this fact: MCAS is real. And it’s quite possible that it’s not as rare as we think. One researcher has estimated that MCAS associated mutations may occur in over 5% of the population (Molderings 2014). If this bears fruit, then these people in your office needing help are only the first wave of a growing population that is allergic to the world. We are off the reservation right now, but these people still need help.

 

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

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, and Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.

Cem Akin, MD, PhD, Peter Valent, MD, Dean D. Metcalfe, MD. Mast cell activation syndrome: Proposed diagnostic criteria. Volume 126, Issue 6, December 2010, Pages 1099–1104.e4

Peter Valent, Cem Akin, Michel Arock, Knut Brockow, Joseph H. Butterfield, Melody C. Carter, Mariana Castells, Luis Escribano, Karin Hartmann, Philip Lieberman, Boguslaw Nedoszytko, Alberto Orfao, Lawrence B. Schwartz, Karl Sotlar, Wolfgang R. Sperr, Massimo Triggiani, Rudolf Valenta, Hans-Peter Horny, Dean D. Metcalfe. 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;157:215–225.

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

 

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Diabetes, mast cells and allergic disease

Patients with either type I or II diabetes mellitus demonstrate unusual physiology pertaining to hypersensitivity and mast cell activation. This was first described in 1962, when a paper reported that diabetic animals do not experience anaphylactic shock.   Despite the amount of time that has passed, the reasons for this are still being unraveled.

The role of mast cells in type II diabetes mellitus is more straightforward. When mice are made obese through dietary manipulation, they normally develop glucose intolerance or insulin resistance. If the mice are mast cell deficient, they do not develop these conditions. Transfer of mast cells to mast cel deficient mice was shown to reverse this protection against these complications.

In mice without established type Ii diabetes that were given manipulated diets to induce obesity, treatment with mast cell stabilizers actually prevented the development of type II diabetes. In mice with pre-established type II diabetes, treatment with mast cell stabilizers cromolyn or ketotifen protected against glucose intolerance and insulin resistance. These findings have been replicated in at least one patient, a type II diabetic who had normalized plasma glucose and A1C after six months on cromolyn.

The relationship between mast cells and type I diabetes is far more intricate.   This is mostly understood through a diabetic rat model. It is possible to induce type I diabetes in rats by administering a chemical called alloxan. Triggering diabetes in this way causes a variety of mast cell changes in these animals. The same changes can be seen when causing diabetes via administration of another chemical, streptozotocin.

Diabetic rats have less vascular response to the action of histamine and reduced mast cell degranulation. These animals are resistant to both local and systemic allergic responses, including anaphylaxis.   Mast cell populations become depleted and less likely to activate. When exposed to antigen, diabetic rats have 50% less degranulated mast cells and histamine release compared to non-diabetic controls.

IgE production is also suppressed in diabetic rats, both antigen specific IgE and total IgE. If you transfer mast cells from the spleen and lymph nodes of non-diabetic rats to diabetic rats, IgE production is diminished. Likewise, if mast cells from diabetic rats are transferred into non-diabetic animals, IgE production is restored.

This protection from allergic processes is well established in animals, but also translates to humans. Children with type I diabetes, and their siblings, are less likely to develop asthma. The incidence of bronchial asthma, rhinitis, and atopic dermatitis is lower than predicted in patients with diabetes mellitus.   Risk of death due to anaphylactic shock is significantly reduced in diabetes. This has been attributed to both the depletion of mast cell populations in diabetics, but also to the overproduction of corticosteroids in the body.

 

References:

Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.

Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.

Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.

Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673

Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2

Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.

Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.

Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.

Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.

S.C. Cavalher-Machado, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.

 

Questions on bone involvement

I wrote these posts in direct response to an email I received from a person in the MastAttack Facebook group (feel free to join) who follows the blog. This person had the following questions:

1) Are osteosclerotic lesions the same as/affiliated with the terms sclerotic, blastic and osteoblast?

Lisa’s response: Sclerotic is associated with the term osteosclerotic. Osteosclerotic means “bone hardening”. Sclerotic can also be used to describe other pathologies, like dermatosclerotic.

Blastic is associated with the term osteoblast, but it can also mean several other cell types. One example of the word “blast” is to mean an immature blood cell. In this context, high levels of blasts can mean severe infection or blood cancers. Osteoblast is the cell type that makes new bone. So osteosclerosis is thought to occur because osteoblasts work faster at laying down new bone than osteoclasts work at eating up old bone.

2) Are osteolytic lesions the same as/affiliated with the terms lytic and osteoclast?

Lisa’s response: Lytic is associated with the term osteolytic. Lytic is the adjective form of lysis, which means to rupture. Osteolysis is caused by two distinct processes occurring together: the first is that rapid growth of abnormal cells (like neoplastic mast cells) inhibits the action of osteoblasts, which normally lay down new bone; and the second is that osteoclast activity is increased, so bone is being absorbed very quickly.

3) If above correlations are correct, A&C below seem contradictory to me, as do B&D.??? Perhaps I’m confused when I isolate it out of context (it was conversation where you were clarifying for someone that osteoporosis wasn’t criteria for SM). (Lisa’s note: Statements A, B, C and D are below these questions for reference.)

Lisa’s response: In multiple studies, patients with ISM, SSM, ASM and SM-AHNMD have been identified as having osteosclerosis. In the largest study (Barete 2010), they found osteosclerosis was more closely associated with aggressive forms of SM (SM-AHNMD and ASM). However, they are still only talking about four people in the aggressive group as opposed to two people in the other (ISM/SSM) group. So in that study, more people with aggressive disease had osteosclerosis than those who had less aggressive disease. In another study, there was no correlation found between osteosclerosis and disease severity.

In particular, what we do not know is whether or not osteosclerosis makes progression more likely by itself. The most robust study found that osteosclerosis in conjunction with swelling of the liver and spleen, presence of multilineage KIT mutation and high increase of baseline serum tryptase warranted careful monitoring for progression. So I’m not convinced that osteosclerosis as a standalone marker is immediately concerning regarding progression, but taken along with these other factors, it may be an indication for cytoreductive therapy.

4) Ultimately, I’m trying to get straight in my mind which is the “worse” lesion (or maybe it’s apples/oranges?) as it pertains to potential progression to an advanced SM category.

Lisa’s response: As pertains to mast cell pathology, large osteolytic lesions are considered the “worst” in that they immediately put you in the ASM category. Again, the only other way this happens is if you have multiple bone breaks as a result of severe osteoporosis (in which osteoporosis is not the qualifier, but the breaks).

So I would consider osteosclerosis as being less severe than osteolytic lesions for the specific purpose of staging SM. However, osteosclerosis is associated with some additional clinical considerations, like blood count abnormalities and higher tryptase, so that should be monitored carefully. Ultimately, this is an issue of research focusing – we need enough time to identify ISM, SSM, ASM and SM-AHNMD patients with osteosclerosis, osteoporosis and osteolysis and determine whether or not osteosclerosis by itself is a determinant of disease progression.

 

Statements:

Note: Both A and B are comments I made as part of a larger FB thread regarding what constitutes “bone involvement” as a diagnostic criterion in staging of SM.

A) Lisa Klimas Osteosclerotic lesions are not immediately a red flag in SM, and about half of SM patients have bone involvement. I wrote a couple of in depth posts about bone manifestations of SM that you may find helpful. I can’t cut and paste in comments on FB for some reason, but google “mastattack bone manifestations of sm” and it comes right up. It’s a two part series.

Lisa’s Response: This was part of a conversation about what constitutes “bone involvement” as a diagnostic marker in staging of SM. It is possible to have ISM or SSM and have osteosclerotic lesions. It does not immediately move you into ASM territory. My phrasing here was poor in that I used bone involvement very broadly (meaning anything involving your bones rather than just the types that affect staging), so that is my fault in that it was confusing.

B) Lisa Klimas Skeletal involvement as applies to mast cell disease means osteolytic lesions, which is a marker for ASM ONLY when you meet the criteria for SM already.

Lisa’s Response: This was part of that same conversation, in which we were discussing bone lesions. One of the markers that qualifies a person as having ASM as opposed to ISM is “bone involvement,” which is defined as large osteolytic lesions or successive fractures due to severe osteoporosis. Here, I was discussing lesions, which is why I omitted the successive fractures. As explained in the earlier part of this post, the osteoporosis does not qualify as “bone involvement” as criteria for ASM – it is the successive fractures.

C) Osteosclerosis is more closely associated with aggressive forms of SM.

Bone manifestations of SM: Part Two

Lisa’s Response: This was in reference to the Barete 2010 paper.

D) (I know these are older articles): “The severity of bone lesions on x-ray correlate with urinary histamine levels. Lytic lesions, which are the predominant finding, have been associated with moderate increases in bone marrow mast cells. Significantly more mast cell infiltration has been correlated with sclerotic ”

Reference: Jianguo Tao, Keith Flaherty and Adam Bagg. Unusual Hematologic Malignancies. Case 1. Hematologic Malignancy Presenting With Diarrhea and Bony Lesions: Systemic Mastocytosis. Journal of Clinical Oncology, Vol 20, No 17 (September 1), 2002: pp 3737-3744

Lisa’s Response: The paper quoted is from 2002 and the reference for this above statement is from 1992. It involved a patient group of nine people. Criteria for SM/ASM/etc were different then. I am waiting on a hard copy of the 1992 paper referenced and will do a follow up post when I have been able to review the primary source. This is the reference for the 1992 paper:

Reference: de Gennes C, Kuntz D, de Vernejoul MC. Bone mastocytosis. A report of nine cases with a bone histomorphometric study. Clin Orthop Relat Res. 1992 Jun; (279):281-91.

Bone involvement in ISM, SSM, SM-AHNMD and ASM: More literature review (part 3)

A 2009 paper looked at prognosis of 157 ISM patients (Escribano 2009). 27% had bone involvement, with 18% patients having osteoporosis, 6% having diffuse bone sclerosis, 4% having patchy bone sclerosis 2% having small osteolysis and 3% having pathological fracture.

A 2012 paper (van der Veer 2012) assessed the frequency of osteoporosis and osteoporotic fractures in a group of 157 ISM patients. They found 28% had osteoporosis, with 27% having osteoporosis of the lumbar spine and 1% having osteoporosis of the hip. 4% had evidence of osteosclerosis.

43% of patients under 50 years old had had at least one fracture (osteoporotic or not) and 61% of patients over 50 years old had had at least one fracture. 27% of patients had one or more vertebral fractures and 21% had non-vertebral, osteoporotic fractures. 23% of male patients under 50 had osteoporosis as well as 38% over 50. 12% of women under 50 had osteoporosis as well as 33% over 50. In total, 37% had osteoporotic fractures. In the group with comorbidities that might cause osteoporosis or fractures, 49% had osteoporotic fractures and 37% had osteoporosis. 59% ISM patients without UP had osteoporotic fractures compared to 28% with UP.

A 2013 paper (Matito 2013) looked at the association of baseline serum tryptase with disease features, including progression to SSM or ASM. 74 patients with ISM were included in the study and were followed for at least 48 months. None of them received cytoreductive therapy. Patients with an increased serum baseline tryptase slope and those without significant tryptase increase had similar prevalence of osteoporosis, patchy bone sclerosis and diffuse bone sclerosis at both presentation and end of study. However, the group with increased serum baseline tryptase was more likely to develop diffuse bone sclerosis in the time span between the beginning of the study and the end of the study (13% vs 2% without significant tryptase increase).

Among the group with low serum baseline tryptase increase, 9% had osteoporosis at the start, and 14% at the end; 5% had patchy osteosclerosis at the end; 2% had diffuse bone sclerosis at the end. None in this group progressed to SSM or ASM.

Among the group with high serum baseline tryptase increase, 10% had osteoporosis at the start, and 16% at the end; 6% had patchy osteosclerosis at the end; 13% had diffuse bone sclerosis at the end. 13% progressed to SSM and 6% to ASM.

Four patients in this study progressed to SSM after the start of the study, in a time ranging from 8-85 months. All had serum baseline tryptase of at least 200 ng/ml and had increased serum baseline tryptase slope. They also had D816V CKIT mutation in cells other than mast cells. Two of these patients progressed to ASM. Both of these patients had diffuse bone sclerosis and swelling of both the liver and spleen. The authors of this paper recommend special attention to the development of hepatomegaly and splenomegaly and diffuse bone sclerosis.

 

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.

Matito A, Morgado JM, Álvarez-Twose I, Laura Sánchez-Muñoz, Pedreira CE, et al. (2013) Serum Tryptase Monitoring in Indolent Systemic Mastocytosis: Association with Disease Features and Patient Outcome. PLoS ONE 8(10): e76116. doi:10.1371/journal.pone.0076116

Escribano L, A lvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish network on mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514–521.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Literature review (part 2)

There have been several publications on bone involvement in SM. Importantly, not all of these papers define SM the same way. Some define it as ISM, while others define it as ISM, SSM, SM-AHNMD and ASM. (I personally am sloppy about not specifying when I mean ISM versus when I mean any all the systemic proliferative groups. So if it’s not clear, please ask.) Another thing to be aware of is that the terminology for osteosclerosis is not consistent. It is sometimes referred to as osteocondensation (this is primarily a term used by French researchers). I have done some digging recently on this and cannot find any indication that these two terms do not represent the same phenomenon (increased deposition of bone), so if anyone knows of any papers or sources that say they are different, please let me know.

A 2010 paper (Barete 2010) defines SM as ISM, SSM, SM-AHNMD and ASM. They divided the study into two groups: Variant 1 (non-aggressive), ISM and SSM; and Variant 2 (aggressive), SM-AHNMD and ASM.

Overall (ISM, SSM, SM-AHNMD and ASM), 49% of patients had some form of bone involvement. Osteoporosis was most common, occurring in 31% of patients. 17% had a vertebral fracture. 8% had osteosclerosis. 4% had a mixed pattern, so more than one type of bone involvement. 5% had osteopenia with a previous fracture (this could be unrelated to mast cell disease, like an arm broken in a fall). Only one patient had a focal area of osteolysis with spontaneous fracture.

56% of variant 2 (aggressive) group had osteoporosis, compared to 23% of variant 1. However, when they excluded people who were classified as variant 2 based upon bone involvement, the association dropped to 17% variant 2 with osteoporosis and 23% of variant 1. Osteoporosis associated with vertebral fracture affected 48% variant 1 and 8% variant 2. Osteoporosis was also found to be associated with fewer GI symptoms, with 39% variant 1 having GI issues while 65% variant 2 did.

A total of six patients (out of a total group of 75) had osteosclerosis. One ISM, one SSM, three ASM and one SM-AHNMD patient had osteosclerosis. This translates to two in the variant 1 group and four in the variant 2 group, so twice as many in the aggressive group (ASM, SM-AHNMD) as in the non-aggressive group. 66% of patients in variant 2 with osteosclerosis had a blood count abnormality (anemia, thrombocytopenia, eosinophilia) vs 12% in variant 1. 83% of patients in variant 2 with osteosclerosis had received cytoreductive therapy vs 33% in variant 1, and higher tryptase level was associated with osteosclerosis. Overall, this means that osteosclerosis was associated with a more severe disease presentation (a patient with ISM and osteosclerosis may have a blood count abnormality), but this study does not provide any insight as to whether osteosclerosis is a marker associated with progression toward ASM or SM-AHNMD.

A 2011 paper (Guillaume 2011) assessed bone involvement in a group of CM and SM patients. In this study, SM included ISM, ASM and SM-AHNMD. 45 patients were included.  They found one patient with osteolysis, eight with osteocondensation (a form of osteosclerosis), four with a mixed pattern and three with fractures. They found no association between the presence of radiologic lesions (lesions detected by imaging techniques) and severity (here classified as non-aggressive: ISM and CM, and advanced: ASM and SM-AHNMD).

This study also looked at chemical markers used for bone remodeling. They found that markers associated with both bone resorption and bone formation were higher in mastocytosis patients than in the general population. The higher levels were thought to represent increased number of osteoblasts and osteoclasts due to the increase in mast cells. Osteoprotegerin was also higher in mastocytosis patients. This is a protein released by osteoblasts that regulates the activity of osteoclasts. Levels of C-telopeptide were significantly higher in patients with SM-AHNMD or ASM than in patients with ISM or CM.

A 2011 paper (Rossini 2011) investigated the relationship between tryptase and bone turnover markers (bone specific alkaline phosphatase, C-telopeptide, osteocalcin) in ISM patients. A total of 82 patients were enrolled in the study. 36% had bone involvement. 20% had osteoporosis, with 18.7% found in the spine and 2.5% at the hip. Five patients had a history of bone breaks outside of the spine. 27 patients had vertebral fractures. Two patients had osteosclerotic features and also had particularly high tryptase levels. Another study previously reported that high tryptase can be associated with increased bone density (Kushnir-Sukhov 2006).

This study had a large amount of ISM patients without skin lesions (55%). A very important finding of this particular study was that ISM patients without skin lesions are at the same risk for osteoporosis. As lesions are often one of the more identifiable markers of mastocytosis, the author raises the very valid point that osteoporosis may in some people be the only sign of latent ISM.

This paper reported that “diffuse osteosclerosis associated with SM is not a[n] “osteopetrosis-like osteopathy”, as previously reported, but a skeletal disease characterized by increased bone turnover.” This is important, as they have previously been equated for lack of distinction. The author further notes that the “pathophysiology of SM-related osteosclerosis remains obscure, although it is known that MCs can exert a direct stimulatory effect on osteoblast proliferation, recruitment, and activity.”

This study found that bone mineral density and serum tryptase did not correlate with the serum markers of bone turnover. However, it did find that ISM patients with osteosclerosis had higher tryptase and bone turnover markers (bone specific alkaline phosphatase and C-telopeptides of type I collagen) than ISM patients with other types of bone involvement.

(Literature review continued tomorrow)

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128:344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

One of the more nuanced aspects of mastocytosis is how it affects bone structure. Previously, it was thought that only patients with systemic mastocytosis experienced bone pain, and that bone pain was always a function of increased proliferation in the marrow. This no longer appears to be the case. Some patients with non-proliferative mast cell disease have been found to experience bone pain, likely as a result of mediator activity on the outside of the bone. In particular, histamine can be very irritating to the cells on the outside of the bone.

Generally speaking, bone cells work like this:

Osteoblasts make new bone. Osteoclasts eat away (resorb) at bone so that new bone can be put in that place. When these processes aren’t balanced, you develop bone conditions.

In osteosclerosis, your body is making new bone faster than it can resorbed. In osteoporosis, your body is resorbing bone faster than new bone is made.   In osteolysis, your body is also resorbing bone faster than new bone is made, but to a much larger extent than usually seen in osteoporosis. Both osteoporosis and osteolysis can cause pathologic fractures, meaning that because your bone is weak from osteoporosis or osteolysis, the bone breaks.

Bone involvement in systemic mastocytosis is important because the type of bone involvement present can be used to stage the disease. Specifically, certain types of bone involvement can cause a person with indolent or smouldering systemic mastocytosis to be reclassified as aggressive systemic mastocytosis (ASM). Osteolysis (in which bone is eaten away) is a marker for ASM. If you have ISM or SSM and are found to have a large osteolytic lesion, you now have ASM.

More confusing is the relationship of osteoporosis to ASM. If you have ISM or SSM AND you have osteoporosis AND you have multiple fractures due to the severity of the osteoporosis (known as pathologic fractures), you are classified as having ASM. There is some debate in the community as to whether or not osteoporosis with successive pathologic fractures is a true indication of ASM. However, it is currently included in the diagnostic guidelines, and so if you meet this criteria while also having ISM or SSM, then you are classified as having ASM.

But I want to be very clear about something: the osteoporosis is NOT the factor that classifies someone as having ASM. It is the MULTIPLE FRACTURES as a result of bone disease that classifies someone as having ASM. So if you have SSM and are diagnosed with osteoporosis and have a single vertebral fracture as a result of osteoporosis, you are NOT classified as having ASM. It is easier I think to consider this “bone involvement” criterion of ASM as osteolysis or multiple fractures due to bone deterioration.

SM is well known as a possible risk factor for osteoporosis. This has been attributed by different groups to either infiltration of bone by mast cells or release of mediators, including histamine, heparin and tryptase. IL-6 levels were also shown to be proportional to disease severity and osteoporosis in mastocytosis patients (Theoharides 2002). Histamine regulates bone resorption by osteoclasts via H1 and H2 receptors (Dobigny 1997). In bone biopsies of osteoporotic patients, the number of osteoclasts is sometimes elevated and sometimes normal.

Up next: literature review of studies on bone involvement in ISM, SSM, SM-AHNMD, and ASM.

 

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Wayward

It is getting to be time to organize my life in anticipation of several weeks of recovery after surgery. I spend a lot of time writing out instructions on how to live my life. When to pay bills. What pills to take. What medical supplies to order. I revise and update crucial documents, slide them into a folder in my filing cabinet. Every important thing about me reduced to some typed words on so many pages.

I can’t be alone for weeks after surgery. The risk of anaphylaxis is too high. One of my best friends took charge of arranging who will stay with me, when and for how long. I have known most of my close friends for the majority of my life. We grew up together, and will grow old together. We have shared so much, all the ebbs and flows of time. And now I’m sick, and we share that.

It is so much to take care of someone like me, with all of my complications. It is something that can only be done out of the most selfless kind of love. When I told my friends that I would need surgery again, they immediately volunteered their time and energy to help me. It is painful to see how readily they offer to be with me during the hardest times of my life.   It makes me feel so much love that I don’t think my heart can take it.

I found some old pictures yesterday, a whole bunch of us in face paint and costumes half a life time ago. It is hard to believe that we were ever so young. It is hard to believe these are the same people who show up over and over to remind me that I am loved. They put me back together, every time.

I have been so fortunate to have people who love me to the point of bending their entire lives to work around the ill fit of my disease. There is no one in the world luckier than me.

When I first got sick, I could never have imagined it would go on so long. I could never have imagined that I would live this way forever. I could never have imagined all the ways I would be made strong by these people.

I didn’t choose this wayward path. But since I am on it, I couldn’t have found a better group of people to travel it with.