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.