Reprinted with the kind permission of Health Rising.
By Remy St Clare
Mast Cell Activation Syndrome is new to the medical profession – much newer than ME/CFS or FM. Diagnostic criteria were only proposed about five years ago and because most doctors don’t know about it, it’s rarely diagnosed.
But it can cause all the symptoms in Never Bet Against Occam: Mast Cell Activation Disease and the Modern Epidemics of Chronic Illness and Medical Complexity,” Dr Lawrence Afrin's new book, and its proponents think it’s much, much commoner than thought. It’s also often associated with POTS, Elhers Danlos Syndrome, Lyme Disease and ME/CFS/FM. Dr. Klimas has called it one of the most interesting immune diseases going.
Allergies are not just itching and trouble breathing or caused by hay fever, bee stings or reactions to shellfish and peanuts. While these are the most common manifestations of allergies, an entirely different allergic process can affect literally every system in your body.
In fact, it can produce among the strangest and widest variety of symptoms of any disease. So many that the people afflicted with these kinds of allergies usually utterly baffle their doctors. Most doctors don’t know anything about them and they are rarely diagnosed. They’re caused by a disorder called Mast Cell Activation Syndrome (MCAS) which features mast cells gone a little crazy.
So what are mast cells?
That is one of the questions that Dr. Lawrence Afrin, a leading expert in the field of mast cell diseases, answers in the new book, Never Bet Against Occam: Mast Cell Activation Disease and the Modern Epidemics of Chronic Illness and Medical Complexity.
Dr. Lawrence Afrin is a board certified hematologist/oncologist who earned his MD at the Medical University of South Carolina and then worked at the University of Minnesota’s Masonic Cancer Center. He wrote the book to highlight this new syndrome and help both doctors and people who suffer begin to identify and treat it better.
Dr. Afrin writes that mast cells “serve largely as sentinels of environmental change and bodily insults.” When those insults occur, they “respond by releasing large and variable assortments of molecular mediators.” These mediators then directly and indirectly influence the behavior of local and distant cells and tissues in order to “maintain, or restore, homeostasis.”
In English, that means mast cells are really common and really important. So much so that they’re often called the master regulators of the immune system. Mast cells come from the bone marrow and are filled with sacs of chemical mediators. Histamine is the most commonly known mediator, but there are countless others.
Mast cells also play an important role in the body’s first line of defense. Their signals recruit other players in the immune system response and help to keep us healthy and free from disease.
Unless it all starts to go wrong.
Systemic Matocytosis (SM)
The closest most doctors come to mast cells in medical school is a disease called Systemic Mastocytosis (SM) They are taught that this rare disease will reveal itself through characteristic staining patterns of mast cells found during a bone marrow biopsy. Other criteria for diagnosis of SM include elevation of an enzyme called tryptase or identification of a genetic mutation called KIT.
Dr. Afrin began to suspect that some portion of mast cell disease might be due to the inappropriate release of chemical mediators from a normal count of mast cells rather than increased numbers of mast cells (SM). Afrin’s hypothesis laid the groundwork for the identification of a spectrum of diseases that make up what is now called Mast Cell Activation Disorder (MCAD).
The markers used to diagnose SM are typically not all that helpful in MCAS. Tryptase, for example, is most often normal. Bone marrow biopsies do not always show the characteristic clumping of mast cells required to meet the diagnostic criteria. Other blood and urine tests may or may not reveal abnormalities. Many tests often need to be repeated during times of a “flare” in symptoms to see the changes characteristic of mast cell diseases. Poor handling of specimens by the laboratory is also a very real issue impeding mast cell disease diagnosis.
But Dr. Afrin shows in Never Bet Against Occam that MCAD is a “real” illness that can affect virtually every system in the body.” He does this by presenting a series of case studies that demonstrates how MCAD looks.
The typical MCAD patient he portrays is very ill and has been written off by the rest of the medical establishment as more trouble than they are worth. Not only does Afrin argue that MCAD is a “real” illness, he believes that it’s epidemic. Early research suggests that as much as 14-17% of the population may be affected, that’s one out of every 6-7 individuals.
So what are the symptoms of MCAD anyway? Could you have MCAD? Do you have typical “allergic” symptoms like flushing? Itchiness? Dizziness? Or GI symptoms like diarrhea, cramping, constipation or nausea? Or less commonly considered allergic symptoms like brain fog?
How about migraines? Sinus infections? Congestion? Dry, gritty eyes? Bone density problems? Bleeding abnormalities – blood either too thick or too thin? Easy bruising? POTS? Orthostatic intolerance? Fatigue? Food, drug, and chemical sensitivities? Feel cold a lot? UTIs/Interstitial Cystitis? Arthritis? Muscle and/or joint pain? Cardiac abnormalities?
Then, perhaps welcome to MCAD! No body system is immune from the effects of this inflammatory disease. Let that statement sink in for a few moments. Read it again, if necessary. Every single system in the body can be affected by aberrant mast cell activity.
To further complicate matters, mast cells don’t always activate the same cytokines in every person. In fact, they very rarely present the same in the same way twice (though there are many commonalities) and can actually cause opposite effects from one patient to the next.
An example of this dichotomy is a patient with hypercoagulable, sticky, thick blood and the next patient who presents with blood clotting problems, both of which, Afrin argues, can be caused by MCAD.
It’s worth noting that mast cells can also cause immune system abnormalities. Hypogammaglobulinemia is common in MCAD; hypergammaglobulinemia less so, but possible. Many people with MCAD are incorrectly diagnosed with Common Variable Immune Deficiency, a condition characterized by low levels of immunoglobulins and a decrease in antibody response to provocation. Many with MCAD also have a long history of infections in their medical files.
Dr. Afrin notes that mast cells can produce basically any and all interleukins known to man (which may go some way towards explaining why no one can find really good data on cytokine production in diseases like ME/CFS).
Dr. Afrin relies on and credits a database called COPE created by Dr. Horst Ibelgaufts for helping him to connect the dots between seemingly disparate symptoms. (As a side note, I highly recommend supporting this database as well. Dr. Ibelgaufts may look a little bit like a serial killer on the Home page, but his work is truly staggering in comprehensiveness and complexity.)
So how is MCAD diagnosed then if so many body systems are involved and typical markers for SM aren’t all that helpful? The most common tests Dr. Afrin uses to diagnose MCAD are those that measure mast cell mediators. They include plasma histamine, n-methylhistamine (24-hr urine), prostaglandins PGD2 and/or 11-b-PGF2a (24-hour urine) (avoid NSAIDs for 5+ days prior), serum chromogranin A (avoid PPIs for 5+ days before testing), plasma heparin (not if on heparin products) and occasionally testing for leukotrienes.
These are not tests general practitioners are typically familiar with and many require special handling and chilling to prevent degradation of the fleeting mast cell mediators.
Therefore, if there is a strong clinical suspicion of MCAD, it may be necessary to repeat the testing several times before happening upon the positive result that confirms the diagnosis.
So you’ve been diagnosed with MCAD, what’s next?
Unfortunately, treatment is mostly by trial and error, though many patients do ultimately see a significant amount of symptomatic relief.
Typically, treatment is focused on reducing the mast cell activity and blocking histamine at the H1 and H2 receptors with antihistamine drugs such as Claritin, Zyrtec or Allegra. Famotidine (Pepcid) is often used as an H2 blocker because it has fewer drug interactions than cimetidine (Tagamet), but either will work.
Often times, antihistamines are taken in 2-3 times the OTC recommended dose in divided doses. There are synergistic effects from taking H1 and H2 blockers together as well that are not achieved by taking either alone. Dr. Afrin provides detailed dosing guidelines in his chapters on treatment.
Mast Cell Stabilizers
Many patients also find that taking a mast cell stabilizer to keep mast cells from acting up is helpful. Some antihistamines, like ketotifen, also have mast cell stabilizing properties. Ketotifen is currently only available in the USA through a compounding pharmacy though it is widely and cheaply available elsewhere in the world as Zaditor.
Cromolyn sodium (Gastrocrom) is the best known example of a pharmaceutical mast cell mediator. It’s available by prescription as oral vials or a nasal spray (NasalCrom). Some people report difficulties starting cromolyn sodium though due to a temporary flaring of symptoms and it is recommended to work up slowly to a final, therapeutic dose. It may take many months to see the benefit of cromolyn sodium treatment because of this.
Quercetin is a mast cell mediator that is available in a supplement form. Quercetin is practically insoluble in water though, so I think it is helpful to choose a form that has been modified to be water soluble for enhanced absorption. (Dr. Afrin does not specify any particular form, however.) Studies have shown quercetin to be equivalent to sodium cromolyn for the purposes of mast cell stabilization. Typical doses seem to range from 500-2000 mg/day.
There are other examples of classes of medications that are occasionally found to be helpful. Some of these include tyrosine kinase inhibitors like imatinib or leukotriene inhibitors like montelukast (Singulair). JAK inhibitors are a new class of medications that may or may not prove useful in treating MCAD as well as TNF blockers. NSAIDs, like aspirin, and benzodiazepines may also have a role in MCAD management. Some patients find improvement, especially with pain symptoms, with hydroxyurea.
Most people with MCAD instinctively learn to avoid their triggers whether they are aware of it or not. Strong smells, heat, and chemicals all can trigger reactions and most patients do better when they avoid these triggers. Some MCAD sufferers have also employed neural retraining techniques to help keep stress from exacerbating mast cell degranulation.
Diet has also been found to play a role in treatment with some patients finding improvement in symptoms after adopting a low-histamine diet. Yasmina Ykelenstam's blog, The Low Histamine Chef, is a good example of someone who has experienced significant symptom relief through dietary changes.
Some patients have their medications compounded to be free of fillers and artificial colors and find that their medications miraculously start working for them instead of against them for once. Dr. Afrin does not recommend any particular diet at this point, though, other than to eat as healthy and balanced of a diet as possible.
Unfortunately, at this point, treatment of MCAD is all about symptom management. Dr. Afrin hopes that someday this will not be the case, but until much more research is done, we are a long way from that point. The good news is that most people generally are able to find a combination of medications that will provide significant symptom relief and many are again able to return to normal lives from debilitating levels of disability and illness.
Dr. Afrin wraps up Never Bet Against Occam by discussing the genetics of mast cell disease. Not much is known currently, but some mast cell mutations have been identified with more surely to follow.
The mast cell gene that has been studied the most in SM is called KIT. KIT regulates the mast cell’s ability to survive, move, grow – and activate, according to Dr. Afrin. The KIT gene is not limited to mast cells though. It is also found in many other type of cells because of its corresponding protein, tyrosine kinase.
Tyrosine kinases regulate growth and differentiation of cells. This may be why drugs like imatinib, a tyrosine kinase inhibitor, have shown some clinical utility in MCAD. Dr. Afrin believes that most cases of MCAD, like SM, are rooted in genetic mutations, but concedes that the science is sparse and that this question has yet to be decided.
Interestingly, Dr. Afrin also notes that MCAD patients often find that the disease “steps up” its baseline level of activation misbehavior after exposure to some sort of stressor. Dr. Afrin hypothesizes that patients may possess one or more inheritable “genetic fragility factors” which interact with different stressors like infection or other traumas to cause the occurrence of even more (non-inheritable) mutations which lead to the wide variety of confounding random mutations that occur later in illness, seemingly at random.
Never Bet Against Occam is 480 pages long, which seems overwhelming at first blush, but Afrin’s writing style is more colloquial at times than scientific. I still spent some time looking up new terms or concepts, but the book kept my interest easily and I finished it much more quickly than other “medical” books of similar lengths. There is also a comprehensive glossary that includes phonetic pronunciations for many unfamiliar words. When you think about it, the book almost by definition HAS to be that long to encompass the dizzying (literally!) array of symptoms that can be traced back to mast cell activation.
My hope is that people will read this book and get tested to find out if they are in the subgroup of ME/CFS that might benefit from this approach to treatment. This book provides an excellent primer for the self-starters among us as well as the open-minded physician who is willing to learn.