October 2014

The speed of falling apart

I saw my GI mast cell specialist today.  I have not been looking forward to this appointment.  I find that whenever the shit hits the fan with my health, it is always him telling me things I don’t want to hear in the small exam room at the end of hall. 

I am having major GI issues.  I am nauseous.  I vomit up most of what I eat.  I am reacting not just to food, but to the actual process of eating.  Beyond this, I have had a major change in lower GI symptoms.  I am bleeding from multiple places and spending a lot of time in the bathroom.  My abdomen is swollen and sore again.  If I lay back, I can literally watch myself digesting. 
We went through all my symptoms.  I told him about my endocrinologist appointment and filled him in on some conversations with my immunologist.  He examined me and palpated my sore abdomen, could feel that my colon was swollen. 
“Your problem is proliferation,” he said.  “If you started with two million mast cells, now you’ve got a hundred. Or more.”  I know.  I didn’t have anything helpful to add.  I really hate when I can’t pull useful more information out of my brain because it doesn’t exist. 
I already have a good surgeon, so he agreed to talk to him and get back to me on who wants to order what.  I will definitely need another colonoscopy with biopsies, at the very least, before they decide what to do for surgery.  He called my GI distress “incredible troubles.”  I laughed when he said it.  “Your troubles, they are incredible,” he clarified.  “A lesser person might not do so well.” But I didn’t feel like I was doing well today.  I wanted to go to sleep, quiet and numb, for as long as I could. 
I have said several times that this has been a strange year.  I feel like I can’t express what I mean by that properly.  While I have gotten sicker this year, I have at the same time found an increasing sense of peace.  I feel like I am helping people, and that was only possible because I am sick.  I learned about mast cell disease because I am sick, and I met all these people because I am sick, and I like this life, that I have because I am sick.  All of this is a side product of being sick. 
I skyped with one of my best friends tonight.  “I feel so guilty because I love what I do and I love all these people but it’s all because I’m sick and I don’t want to be sick anymore,” I cried to her.  I had a good long cry.  It was one of those days. 
But in the dark moments, when it feels like my soul is trying to swallow itself whole, I remember this year, and how as time goes on, I somehow feel less and less at odds with my disease.  I somehow feel the anger subsiding, feel this overwhelming calm as I learn how to live in this body each day. 
This year has been weird.  I am self actualizing at the speed of my body falling apart.

Mast cells and metabolic syndrome: Hypertension, obesity and atherosclerosis

Metabolic syndrome is defined as impaired glucose tolerance (IGT) or type 2 diabetes and/or insulin resistance with two or more of the following findings:

1.       Abdominal obesity, defined as a BMI 30; and/or waist to hip ratio >0.90 in men and >0.85 in women
2.       Baseline blood pressure >160/90 mm Hg
3.       Increased plasma triglycerides >1.7 mmol/L; and/or low levels of HDL cholesterol (<0.9 mmol/L in men; <1.0 mmol/L in women
4.       Microalbuminuria (overnight urinary albumin excretion rate > equal to 20 ug/min.)
Inflammation is a known effector of obesity.  Microscopic examination of obese adipose tissue reveals chronic inflammation and excessive amounts of white blood cells, leukocytes.  Macrophages, white cells that are very important in the inflammatory response, are found in adipose tissue in numbers that are directly proportional to the degree of obesity.  T cells, other white cells, also accumulate in adipose tissue. 
Until recently, most of the research on inflammatory cells in adipose tissue focused on macrophages and T cells.  However, we now know that mast cells congregate in larger than normal numbers in white adipose tissue in obese patients.  These patients also demonstrate a higher serum tryptase concentration than in lean individuals.  Mast cells are usually found near microvessels, very small blood vessels, in white adipose tissue.  The number of microvessels correlate with mast cell count in the tissue, implying that a relation between the microvessels and mast cells.
Mast cells release many chemicals, including TNF (tumor necrosis factor.)  TNF is known to mediate insulin resistance, and is overexpressed in white adipose tissue in obese patients.  Treatment with TNF blockers in patients with inflammatory diseases has demonstrated a significant reduction of blood insulin levels as well as the insulin/glucose index.  Several other mast cell mediators contribute to insulin resistance in fat cells, including IL-6, iNOS, MCP-1 and IL-1. 
Research has shown that mast cell stabilizers, cromolyn and ketotifen, can prevent diet induced obesity and diabetes.  In mice, these medications have been able to reverse obesity and diabetes, as well as reducing body weight and glucose intolerance.  These findings have been very exciting for mast cell patients with diabetes.
It is important to know that while metabolic syndrome is usually associated with obesity, patients of normal weight may also be insulin resistant and have metabolic syndrome.
Hypertension (high blood pressure( in mast cell disease is a topic of a lot of recent debate.  In spontaneously hypertensive rats (SHR), the density of cardiac mast cells is significantly higher than normal immediately after birth.  Throughout life, cardiac mast cell density is much higher in these rats than in controls of the same age.  Mast cell chemicals TNF, NF-kB and IL-6 were overexpressed in these rats even before they became hypertensive.  In later stages of hypertension, hearts of these rats showed increased areas of fibrosis in the heart.  These areas of fibrosis were full of activated mast cells.  Expression of two mast cell chemicals, TGF-B1 and bFGF (basic fibroblast growth factor) is much higher than normal in aging and failing hearts in spontaneously hypertensive rats. 
Importantly, mast cell stabilizer nedocromil was able to prevent fibrosis in SHR rats.  Tryptase levels were elevated in SHRs that were not receiving treatment, but returned to normal after treatment with nedocromil.  In untreated SHRs, levels of interferon gamma and IL-4 were elevated, while IL-6 and IL-10 were lower than normal.  All of these levels normalized after treatment with nedocromil.  This medication also prevented macrophage infiltration in the heart ventricle.  This finding indicates that mast cell signaling to macrophages is an important process in fibrosis.
Atherosclerosis is the accumulation of low density lipoprotein (LDL) cholesterol in the arterial wall.  Macrophages eat particles of LDL, and when they do, they turn into weird looking cells called foam cells.  Mast cells often live very close by foam cells, and many researchers think that mast cells help macrophages transform into foam cells. 
When mast cells release chemicals, chymase and carboxypeptidase A are bound to heparin.  After release, these components form insoluble granules called remnants.  When mast cells are activated, LDL uptake by macrophages rises by 7-24X.  Treatment with cromolyn has been shown to block mast cell dependent LDL uptake by macrophages. 
HDL passes from the bloodstream into the arterial wall.  When mast cells degranulate, those remnants degrade HDL components in the blood, peritoneal fluid and maybe also in atherosclerotic lesions.  Mast cell deficient mice have lower serum total cholesterol, triglycerides, phospholipids and a less atherogenic lipoprotein profile in general.
Mast cells are heavily involved in obesity, hypertension and atherosclerosis.  For this reason, many mast cell patients have these problems. 

Reference:

Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.

Metabolic issues associated with MCAS

MCAS patients often have a whole host of metabolic irregularities.  Abnormal levels of electrolytes are very common, as are mild increases in liver function tests, including aspartate transaminase, alanine transaminase and alkaline phosphatase.  Magnesium levels low enough to cause symptoms is not common, although the reason for this is not known.
Vitamin D deficiency is often present in MCAS.  In one study looking at children with asthma, low vitamin D was correlated with decreased lung function and exercise sensitivity.  In MCAS patients, there is no obvious relation to osteoporosis.  Many people receive vitamin D supplements to correct low levels, but it is not clear if there is any benefit to this.

Hypothyroidism (including Hashimoto’s thyroiditis) and elevated levels of TSH are often seen in MCAS patients.  Previous studies have linked hypothyroidism to increased mast cells in bone marrow.  In mice, TSH has shown to increase both the mast cell population in the thyroid and to trigger degranulation.  Hyperthyroidism is sometimes seen in MCAS patients, but much less frequently.  Antithyroid antibodies (TPO) are often high, sometimes extremely high, and sometimes without obvious clinical thyroid disease.

Hyperferritinemia is not unusual in mast cell disease, including MCAS.  18% of ISM patients have high serum levels of ferritin.  It is often misinterpreted as hemochromatosis, even in the absence of the HFE mutation.  MCAS patients with a history of red cell transfusion are often told they have hemosiderosis, even when serum ferritin is much higher than to be expected from hemosiderosis.  High ferritin in MCAS patients is probably secondary to systemic inflammation.  The widely variable nature of the ferritin levels is indicative of inflammation.
MCAS is also associated with obesity and diabetes mellitus (types I and II), all of which are systemic inflammatory conditions.  MCAS patients often have lipid abnormalities.  Hypertriglyceridemia is the most common presentation, but there are many variations.  Lipid issues that have been resistant to treatment with statins are often reversed quickly when MCAS patients are effectively managing their mast cell issues. 
MCAS is also heavily associated with metabolic syndrome.  (There will be a full post on this tomorrow.)

References:
Afrin, Larry B.  Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
A Melander, C Owman, F Sundler.  TSH-induced appearance and stimulation of amine-containing mast cells in the mouse thyroid.  Endocrinology, 89 (1971), pp. 528–533

Siebler T, Robson H, Bromley M, Stevens DA, Shalet SM, Williams GR.  Thyroid status affects number and localization of thyroid hormone receptor expressing mast cells in bone marrow.  Bone. 2002 Jan;30(1):259-66.

Chinellato I, Piazza M, Sandri M, Peroni DG, Cardinale F, Piacentini GL, Boner AL.  Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma.  Eur Respir J. 2011 Jun;37(6):1366-70. 

Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.

Genetics of MCAS: mutations and methylation

Despite having largely the same symptom profile as SM patients, people with MCAS often lack the signature D816V mutation, considered by many to be a marker of clonality and thus proliferation.  Despite the fact that their mast cells may look normal under a microscope, there is now a growing body of evidence indicating that mast cells in MCAS patients behave aberrantly due to mutations aside from D816V. 
In three studies that look at KIT mutations in MCAS patients, they were found in 26.5%, 44% and 65% of patients, respectively.  Even the average of these three values represents a significant number of people with MCAS who have KIT mutations.  Of note, these mutations are mostly outside of exon 17, where the D816V mutation is found.  In one patient, a mutation was found in the NLRP3 gene, associated with the inflammatory response. 
There are a number of other mutations in genes with various functions commonly found in patients with SM.  These include genes that make proteins to regulate other genes and genes that affect how we make proteins (epigenetic regulatory proteins, splicing machinery and transcription factors.)  To date, there have been no studies looking at whether MCAS patients have similar mutations.  However, there are clear hints that they do. 
The mutations previously mentioned were all somatic and not germline.  This means that the mutations arose after early embryonic development and thus were not heritable.  This fact indicates clearly that there are other germline mutations not yet identified that may induce the subsequent mutations.  This has been bolstered by a 2013 paper that found familial clustering in MCAS patients.   
An important finding is that nearly all mutations found in MCAS patients are heterozygous, meaning only one of the two copies was mutated.  This implies that homozygous mutations, in which both copies are mutated, could cause the cell to die.  Alternatively, the various mutations may work together to make the mutations work as strongly as if there were two mutated copies. 
At CpG sites, the cell can add a special marker to the cytosine called a methyl group.  This is called methylation.  If the cytosine in a gene is methylated, it turns the gene off.  When a gene is turned off, your body will not use that gene or make a protein from it.  This is one type of gene regulation (epigenetics.) 
Looking at the methylation status in the genomic DNA of white blood cells from MCAS patients shows aberrant methylation patterns.  The genes incorrectly methylated included some involved in DNA/RNA repair, DNA/RNA processing, cell death, cell activity and communication with other cells.  195 individual CpG sites have been identified as candidates as markers for MCAS.  Importantly, there is a correlation between the age of symptom onset and the year of birth, which indicates a sort of anticipation of developing MCAS.  This means that gene regulation by methylation could affect acquisition of later, non-heritable mutations like the ones seen in KIT.
A gene is made up of introns and exons.  When an RNA code is made from a gene to tell the cell how to make a protein, the cell cuts out some pieces of that RNA.  These pieces are called introns.  The remaining pieces, which are connected back together, are called exons.  The way the cell cuts the RNA and reconnects the pieces is called splicing.   The mutations in KIT seen in MCAS patients almost all involve intron and exon junctions, where they meet.  There are also some differences in the way splicing occurs in MCAS patients. 

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

Constitutional symptoms of MCAS


Constitutional symptoms are any symptoms that affect the function of several systems at once.  They are often nonspecific and can be attributed to many causes, complicating diagnosis. For many people with MCAS, the constitutional symptoms present first and with the greatest frequency.

Fatigue and malaise (the feeling of being “out of it”) are the most common symptoms reported in MCAS patients.  While many patients with these symptoms remain functional, for some, it can be truly, severely disabling, with some patients sleeping for the majority of the day.  Dr. Afrin has referred to stories of “patients in their twenties acting like they are in their eighties.”  Chronic fatigue syndrome, in which patients have severe fatigue unrelated to exertion, not relieved by rest and unrelated to other medical conditions, has been tentatively linked to mast cell activation by Dr. Theoharides. 

I see a lot of discussion about whether or not fevers are part of MCAS.  It depends which researcher is reporting information.  Castells feels strongly that fevers are not part of MCAS symptomology, while Afrin and Molderings feel that they are.  They report that intermittent elevated temperatures are not unusual.  These temperatures are low-grade temperatures, with frank fever being quite rare.  MCAS patients often report constantly feeling cold, though chills and shaking is less common.

I know that one of the ways I can tell my mast cell disease is ramping up is by severe night sweats.  This is apparently common in most presentations of mast cell disease.  As such, many MCAS patients have severe, unprovoked sweating, often overnight, sometimes not.  Some patients report a circadian rhythm.  Furthermore, this sweating is often accompanied by swollen or tender lymph nodes.  When these two symptoms are taken together, usually infection or lymphoma is suspected.  Once these are ruled out, patients are often left with no relief for this frustrating symptom.

Some patients report lack of desire to eat.  Some report quickly feeling full (early satiety.)  In some of these patients, the root cause is a swollen spleen.  A minority of MCAS patients lose weight due to their disease.

Weight gain in MCAS patients is far more common than weight loss.  It often begins suddenly and progresses rapidly, in the absence of dietary or activity changes.  This is partially due to the fluid dynamics of edema due to mast cell activation.  Less often, weight gain is from ascites (free fluid in the abdomen) or serositis, inflammation of the serous tissues, including the pleura (tissue lining the lungs), pericardium (the compartment containing the heart and origination of the large vessels connecting to the heart) and the peritoneum (tissue lining the abdomen.) 

However, the gain in adipose (fat) tissue seems to be responsible for most of the persistent weight gain.  Some patients gain more than 50kg in a year despite significant caloric restriction and frequent exercise.  Many people (and their providers) often attribute their worsening symptoms to the gained weight.  Some people undergo bariatric surgery and despite initial losses, regain the weight, with no improvement of other symptoms.

Pruritis (itching) is very common in MCAS.  Its presentation is varied; episodic or constant; local or diffuse; migratory or not; tolerable or disabling.   

The hallmark of MCAS is that patients invariably present with a collection of “sensitivities.”  These include severe or bizarre reactions to virtually anything, including drugs, food and environemental triggers.  Environmental triggers can be due to the presence of common allergens, physical (such as heat), electrical (such as generation of electrical charge when brushing hair) and even osmotic.  Exposure to harmless microorganisms can cause severe reactions.  Summers are often difficult for MCAS patients due to heat and increased UV exposure, while spring and fall are difficult due to pervasive pollen.  Triggers can cause reactions when the patient touches, inhales or ingests them. 

Though less of a problem than heat, exposure to cold can trigger a hyperadrenergic response that will fuel mast cell activation.  Care must be taken to avoid temperature extremes on either end of the spectrum.

Drug sensitivities are often found to be due to an inactive ingredient in the formulation.  Compounding is an important tool for MCAS patients.  Lactose monohydrate and potato are common fillers for MCAS patients.  Reconstitution at time of use with water is also not uncommon.

 

Reference:

Afrin, Lawrence B.  Presentation, Diagnosis and Management of Mast Cell Activation Syndrome.  2013.  Mast Cells.