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.

Heritable mutations in mastocytosis

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

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

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

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

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

 

References:

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

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

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

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

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

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

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

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

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

Food allergy series: Mast cell food reactions and the low histamine diet

When I started my posts on food allergies, I listed out the causes of food hypersensitivity. Notably absent from this list was mast cell disease. Even among detailed publications on mast cell disease, food reactions are often unmentioned (though potentially subsequent anaphylaxis is usually included.) Unfortunately, food reactions in mast cell disease are still not well understood. Even among experts, the nature and importance of food reactions in overall disease is the subject of much disagreement. Some contend that food reactions are a manifestation of general mast cell reactivity, while some think the foods specifically are sources of reactions. Following this logic, some experts believe in the validity of observing a low histamine diet while others do not.

So please keep in mind that the science behind the low histamine diet is not well accepted or even well defined. I’m going to give you my general comments on the low histamine diet, how I eat and how it has worked for me. It is my personal opinion.

A low histamine diet is one which eliminates or minimizes histamine in the food consumed. I have talked at great length about histamine so I’m not going to reiterate that here. What I will say is that exogenous histamine has been shown to induce mast cell degranulation, which means that histamine from an outside source can cause degranulation. It makes sense to me as a scientist that eating histamine rich foods will cause mast cell degranulation. It especially makes sense because the most commonly problematic food substances for mast cell patients, like alcohol, vinegar and aged cheeses, are major degranulators. I have never been able to tolerate alcohol, so it made sense to me that it was because of degranulation. Again, I prefer to lean on good studies, but in the absence of that, I will accept my own experience living in this body.

Last winter, I was in a lot of pain and generally having a sucky time of life. One of the changes I discussed with my doctors was the low histamine diet. It was in the “this can’t hurt” category. I had put off elimination dieting for a long time due to time and financial constraints, but it seemed like the appropriate time to do it had arrived.

One of the first things that became aware to me was that there is no universally agreed upon low histamine diet. There are lots of websites that discuss it and lay out diet guidelines and none of them are in complete agreement. So I just picked the one that seemed the most reasonable to me and went from there. As a mast cell patient, any diet you pick will require customization.

The diet I picked was the Histamine and Tyramine Restricted Diet by Janice Joneja. It can be found on the Mastocytosis Society Canada page.   I like this diet a lot. I do not know Dr. Joneja personally, but when I read diet/nutrition articles by her, I find them to be based in science. They meet my common sense rule. I’m going to summarize the general guidelines of the diet below along with my comments.

Key guidelines for a low histamine diet:

  • Anything fermented should be avoided. Fermentation produces histamine as a side product. Some are only sensitive to yeast fermented products while some find that fermentation from any organism is triggering.
  • No preservatives and no dyes.
  • No leftovers and nothing overly ripe. This is one of the harder parts of this diet, but I find it very important. Fresh or frozen products seem okay. I have mixed success with thawing frozen meat, but lots of people do it successfully. The key is to not cook something, put it in the fridge and eat it three days later.
  • No canned products.
  • No pickled products.

Milk and milk products: Avoid fermented products, like cheeses of all kinds, kefir, yogurt, sour cream, cottage cheese and cream cheese. A fair amount of milk products are allowed. Milk (cow, goat, coconut) is allowed, as are cheese type products that are made without fermentation (mascarpone, ricotta, panir.) Some versions of this diet allow mozzarella cheese and I find that it is safe for me. Ice cream is allowed if it doesn’t contain other disallowed ingredients. Cream products are okay, too.

Grains, breads: Yeast is the component most likely to be triggering in these products. Many people choose to restrict gluten due to their individual biologic reactions to it. Gluten is not specifically restricted on this diet, but I can tell you that it basically ends up being excluded anyway because gluten containing products usually also contain yeast. Pure, unbleached flour or grain of any kind is allowed. Products that use baking powder for leavening are allowed, like biscuits, soda bread, scones and muffins. Crackers without yeast are allowed, as are cereals if they don’t contain excluded ingredients, including artificial dyes or preservatives. I have a very difficult time finding low histamine baked products that are premade, so I generally make my own. It is surprisingly easy to make good tasting baked products with safe ingredients at home.

Vegetables: The list of vegetables that aren’t allowed feels really disjointed and counterintuitive. There is not much to do beyond committing it to memory. Not allowed: potato, avocado, green beans, eggplant, pumpkin, sauerkraut, spinach, sweet potato, tomato, any overly ripe vegetable. I personally can eat potato and sweet potato without any problem and do pretty much every day. Removing tomato was a revelation for me. It’s hard to live around because we use it for so much, but I really feel so much better. I will sometimes have a little for immediately get a stuffy nose and headache. All other vegetables are allowed. Any green that is NOT spinach is allowed. I eat a huge amount of squash, which is a really versatile ingredient. I get lots of different types from supermarkets or farmers’ markets and I make soups, purees, baked squash, squash lasagna, squash steaks, and a million other things. I can always tolerate it. This diet has also pushed me to get familiar with less common ingredients, like taro root, breadfruit and lotus root.

Fruits: Again, the list of fruits that aren’t allowed doesn’t provide any obvious unifying factor to quickly identify something as safe or not. Not allowed: citrus fruits, including lemon and lime; berries, including cranberries, blueberries, blackberries, gooseberries, loganberries, raspberries, strawberries; stone fruits, including apricots, cherries, nectarines, peaches, plums, prunes; bananas, grapes, currants, dates, papayas, pineapples, raisins. Allowed fruits: melons (keep in mind that some people may have an oral allergy syndrome reaction to melons), apple, pear, fig, kiwi, mango, passion fruit, rhubarb, starfruit (not safe for those with impaired kidney function), longans, lychees. I eat a lot of fruit, especially apples and mangoes.

Meat, fish and eggs: All shellfish are prohibited. They naturally have a huge amount of histamine. No processed meats (cold cuts.) Eggs are allowed if they are allowed. Raw egg white is a HUGE histamine liberator. Fish is allowed ONLY IF IT IS FRESHLY CAUGHT, GUTTED AND COOKED. There are differing opinions on what this means but several sources estimate it must be cooked in less than 30 minutes from catching. So unless you are or are married to a fisherman/woman, I think this is unlikely to happen. Any meat should be fresh or thawed from frozen. Leftover meat should not be consumed.

Legumes: Soy is the big culprit here because it’s in everything and is not allowed. Also not allowed: green peas, sugar or sweet peas, red beans and tofu. Everything else is allowed, including lima beans, chickpeas (I eat a ton of chickpeas), pinto beans, white beans, navy beans, black eyed peas, black beans, lentils (I also eat a ton of lentils), split peas, peanuts, and real peanut butter.

Nuts and seeds: All okay except for walnuts and pecans.

Oils: All okay except for oils that contain preservatives like BHA or BHT.

Spices: No anise, cinnamon, clove, curry, cayenne, nutmeg. Everything else is okay.

Sweeteners: No unpasteurized honey, chocolate, cocoa beans, cocoa. Most others are fine, including pasteurized honey, sugar (of really any kind), maple syrup, pure jams and jellies. This diet says plain, artificial sweeteners are okay. They are definitely not for me. One of the very first things I was told by mast cell specialist was not to use artificial sweeteners. So you can judge for yourself.

Drinks: A lot of drinks are restricted, including all teas. Most fruit juices and drinks have some type of unapproved ingredient. Milk, pure juices, water, mineral water and coffee are the allowed drinks. I also sometimes make “muddled” drinks where I crush some safe fruit with a mortar and pestle, make a simple syrup, and then put the muddled fruit in some soda water with some simple syrup.

Miscellaneous: Not allowed: Yeasts, yeast extract, all vinegars, flavored gelatin. Allowed: plain gelatin, cream of tartar, baking soda and baking powder.

The diet recommends a strict four week adherence to determine if it works. I think this is pretty accurate. I did it with no cheating for five weeks. It helped a lot. I slept better, I wasn’t swollen all the time and I was less nauseous. But there were some downsides. The first is that it is a royal pain in the ass if you work because you really have to cook every day. The restrictions on meat meant that I had meat about once every 2-3 weeks. Not everything freezes well so making a lot ahead of time isn’t always a good idea.

Finding recipes can be hard because the fact that they are labelled low histamine does not mean that they ARE low histamine. Please be very careful with that. I also find that some sources for low histamine recipes seem to assume a high level of economic freedom in food purchasing, as well as access to expensive and difficult to find ingredients. I can shop at Whole Foods, which has a knowledgeable staff and a good stock of ingredients for diets like these. There were several components I still cannot find. I also spent literally $1000 at Whole Foods for the five weeks when I initially did this diet.

One unexpected result of this diet was that it resensitized me to foods that I had become desensitized to. So foods that used to bother me a little now cause a severe reaction (sometimes anaphylactic, requiring epinephrine.) I understand that the reason for this is because these foods always caused reactions but I was effectively “used” to them so I didn’t notice. Regardless of the reason, my life is a lot more difficult foodwise than it used to be. I can “cheat” with some foods with medications but the reactions are still bad. I don’t always know how I feel about my choice to do the low histamine diet in my particular situation, but the fact is that since I did, I now am forced to observe a version of it, probably for life.

So that’s my run down on the low histamine diet.

 

 

Lesser known mast cell mediators (Part 3)

Substance P is a neurotransmitter and modulates neurologic responses. It is found in many sensory nerves as well as the brain and spinal cord. It participates in inflammatory responses and is important in pain perception. It is involved in mood disorders, anxiety, stress, nerve growth, respiration, neurotoxicity, nausea, vomiting and pain perception. Its release from nerve fibers into the skin, muscle and joints is thought to cause neurogenic inflammation.

Urocortin is related to corticotropin releasing factor (CRF.) It strongly suppresses blood pressure and increases coronary blood flow. It is thought to have a role in increasing appetite during times of stress.

VEGF-A (vascular endothelial growth factor A) is a member of the platelet derived growth factor (PDGF)/VEGF family. It is important in nerve biology and is the substance mainly involved in inducing growth of blood vessels. It is heavily involved in diseases that involve blood vessels, like diabetic retinopathy and macular degeneration. It is a vasodilator and increases permeability of the smaller vessels.

VIP (vasoactive intestinal peptide) is a small protein like molecule used by nerve cells for communication. It stimulates heart contraction, vasodilation, lowers blood pressure, and relaxes the smooth muscles of the trachea, stomach and gall bladder. It also inhibits gastric acid secretion and absorption in the intestine.

Mast cell kininogenase removes a portion of a compound to release active bradykinin. This is important in the kinin system.

Phospholipase A2 promotes inflammation by initiating formation of arachidonic acid, the precursor needed to form many inflammatory molecules, including prostaglandins. Excessive levels of phospholipase A2 can lead to increased vascular inflammation, such as a seen in coronary artery disease and acute coronary syndrome. Elevated PLA2 is found in the cerebrospinal fluid of people with Alzheimer’s disease and multiple sclerosis.

Corticotropin releasing hormone (CRH) is a hormone and neurotransmitter. High CRH levels have been associated with Alzheimer’s disease and severe depression. CRH is produced in the hypothalamus and is carried to the pituitary gland, where it stimulates secretion of adrenocorticotropic hormone (ACTH.) ACTH drives synthesis of cortisol and other steroids. Imbalance of these hormones can have dire consequences.

Endothelin is the most potent vasoconstrictor currently described. It raises blood pressure and if uncontrolled, hypertension may result. It is involved in many disease processes, including cardiac hypertrophy, type II diabetes and Hirschsprung disease.

Chondroitin is found largely in connective tissues and is a principal component of cartilage. It is typically bound to other components when released from mast cells and interacts with a variety of molecules.

Hyaluronic acid is widely found in epithelial, neural and connective tissues. It participates in a variety of reactions and sees significant turnover daily. When hyaluronic acid is degraded as part of the turnover, its degradation products can cause inflammatory responses.

Lesser known mast cell mediators (Part 2)

Arylsulfatase A, also called cerebroside sulfatase, breaks down compounds to yield cerebrosides and sulfates. Cerebrosides can be either galactocerebrosides, which are found in all tissues of the nervous system; or glucocerebrosides, which are found in the skin, spleen, red blood cells and, to a lesser extent, tissues of the nervous system.

Arylsulfatase B, which has several other names, breaks down large sugar compounds, especially dermatan sulfate and chondroitin sulfate. Arylsulfatase B is mostly found in the liver, pancreas and kidneys.

Mutations in the gene for either arylsulfatase can lead to a variety of heritable disorders, including mucopolysaccharidosis VI and metachromatic leukodystrophy.

Chymases include mast cell protease 1, mast cell serine proteinase, skeletal muscle protease and so on. They are found almost exclusively in mast cells, but are present in small amounts in the granules of basophils. They have several functions, including generating an inflammatory response to parasites. They convert angiotension I to angiotensin II and therefore impact hypertension and atherosclerosis.

Bradykinin causes dilation of blood vessels, which induces a corresponding drop in blood pressure. It achieves its action by triggering release of prostacyclin, nitric oxide and endothelium derived hyperpolarizing factor. It also causes contraction of non-vascular smooth muscles in the respiratory and GI tracts, and is involved in the way the body senses pain. Bradykinin is important in angioedema.

Angiogenin, also called ribonuclease 5, stimulates the formation of new blood vessels. It drives the degradation of the basement membrane and local matrix so that endothelial cells can move toward the vascular spaces.

Leptin is the hormone that regulates hunger. It is mostly produced by fat cells, but is released by mast cells as well. When a specific amount of fat is stored in the body, leptin is secreted and tells the brain that it is full. It opposes the action of ghrelin, the hormone that tells your body it is hungry.

Renin, also called angiotensinogenase, is a critical component of the renin-angiotension system (RAS) that controls the volume of fluids not in cells, including blood plasma, lymph and interstitial fluid. It regulates the body’s mean arterial blood pressure. It converts angiotensinogen to angiotensin I.

Somatostatin, also growth hormone inhibiting hormone (GHIH), regulates the endocrine system, transmission of neurologic signals and cell growth by acting on somatostatin receptors and inhibiting the release of various secondary hormones. It inhibits secretion of glucagon and insulin. It is secreted throughout the GI system and decreases stomach acid production by downregulating the release of gastrin, secretin and histamine.

Lesser known mast cell mediators (Part 1)

I have posted at length about the roles of histamine and serotonin. Here are some less well known mast cell mediators. I will be doing in depth posts on the more relevant substances in the near future.

Monocyte chemotactic protein 1 (MCP-1), also known as chemokine ligand 2 (CCL2), draws other white blood cells, including memory T cells, monocytes and dendritic cells, to the site of injury or infection. It has important functions in neuroinflammation as seen in experimental autoimmune encephalitis, traumatic brain injuries, epilepsy and Alzheimer’s disease; and in diseases with pathologic infiltration of monocytes, like rheumatoid arthritis.

Chemokine ligand 3 (CCP7) recruits monocytes and regulates macrophage activity. It is known to interact with MMP2.

MMP2 (matrix metalloproteinase 2) is involved in tissue remodeling, reproduction and fetal development. It degrades type IV collagen. It has regulatory effects on the menstrual cycle and has been tied to growth of new blood vessels.

Interleukin 8 (IL-8), also known as neutrophil chemotactic factor (NCF), draws other white cells, mostly neutrophils, to a site of infection. It can activate multiple cells types, including mast cells, and promotes degranulation. It has been linked to bronchiolitis, psoriasis and inflammation.

MCP-4 (CCL13) attracts T lymphocytes, eosinophils, monocytes and basophils to an area of inflammation. Improper regulation can exacerbate asthma symptoms. Mast cells can release MCP-1 when stimulated by TNF-a and IL-1.

CCL5 (RANTES) attracts T cells, eosinophils and basophils. When IL-2 and interferon-γ are present, CCL5 activates natural killer cells and causes proliferation of the same. It is also important in bone metabolism.

CCL11 (eotaxin-1) specifically recruits eosinophils and is heavily involved in allergic inflammatory responses.

CPA3 (carboxypeptidase A3) digests proteins. It is released complexed with heparin proteoglycan along with chymase and tryptase.

Both interferon α (IFN- α) and interferon β (IFN-β) are made in response to viral infections. Their activities are regulated by IFN- γ. IFN- γ also draws white cells to the site of inflammation. Failure to properly regulate interferon levels can cause autoimmune disease. Interferons are so called because of their ability to “interfere” with viral infection. They are responsible for “flu type symptoms,” such as fever, muscle aches and lethargy.

All mediators listed here are produced by mast cells and stored in granules until degranulation.

 

MCAS: GI Symptoms and Liver Abnormalities

MCAS patients suffer a variety of GI ailments, which are largely in common with SM.

Aerophagia, excessive swallowing of air, is very common. It is not entirely obvious why this occurs. In other patient populations, aerophagia is usually due to poor coordination between swallowing and respiration. Severe cases can lead to abdominal distention, aspiration of stomach contents into the lungs and esophageal rupture.

Chest discomfort is common in MCAS. Cardiac issues should be ruled out, but in most people, it is due to esophagitis. Some patients have a previous diagnosis of reflux but it is refractory to all relevant treatments.

Diarrhea and constipation, sometimes alternative, are very common. In one study, 89% of MCAS patients studied had frequent nausea, 100% had abdominal pain of some nature, and 69% had noncardiac chest pain. Partial bowel obstructions are uncommon, but do occur in MCAS. They are thought to be due to focal dysmotility or focal edema.

IBS is a frequent previous diagnosis in MCAS. The GI tract often looks normal by eye and typical H&E staining shows mild inflammation. Staining for mast cells often shows they are increased. Of note, there is not a universal consensus on what is considered “increased mast cells” in GI samples. Generally, above 20 cells per hpf is marked as high by pathologists. Presence of the D816V CKIT mutation is rare in GI biopsies of MCAS patients.

Selective malabsorption of certain nutrients is often seen in MCAS. Iron malabsorption is by far the most common. Copper and B vitamins are often poorly absorbed as well. Protein calorie malabsorption is rare, but leads to weight loss and wasting.

Pancreatic enzyme supplementation can be helpful in treatment of diarrhea, weight loss and malabsorption. The fact that this often works suggests that MCAS driven inflammation or fibrosis causes pancreatic exocrine deficiency, a condition in which the pancreas does not make enough digestive enzymes. Mast cells have a known link to painful chronic pancreatitis. In patients with painful vs painless chronic pancreatitis, mast cell density is 3.5X higher in pancreas biopsy.

About half of MCAS patients have some kind of liver abnormality. Fibrosis (obliterative portal venopathy) is the most common. However, fatty metamorphosis, sinusoidal dilatation, venoocclusive dilatation, nodular regenerative hyperplasia and cirrhosis have also been seen. Sterile (non-infectious) inflammation of the liver and portal trial infiltration by lymphocytes and eosinophils has also been identified in a number of patients. In particular, these patients often have a 2-3X elevation in transaminases and/or alkaline phosphatase, determinants of liver function. Impeded flow of bile from the liver is usually absent. Portal hypertension is unusual but has occurred, causing swelling of the spleen and varices in the esophagus. Rarely, free fluid in the abdomen (ascites) has occurred in MCAS patients.

One study found that 75% of MCAS patients tested had high cholesterol levels. Importantly, 79% of patients had “normal” BMI or were underweight, so the high cholesterol was not correlated to weight. 44% had a twofold or greater elevation of liver enzymes. 36% had increased bilirubin in the blood. 15% had fatty liver; 13% had swelling of the liver; 4% had cysts; 4% had adenomas; 2% had hemangiomas. 14% of patients had pancreatic involvement with elevated lipase or amylase.

 

References:

Kirsten Alfter, Ivar von Ku gelgen, Britta Haenisch, Thomas Frieling, Alexandra Hu lsdonk, Ulrike Haars, Arndt Rolfs, Gerhard Noe, Ulrich W. Kolck, Jurgen Homann and Gerhard J. Molderings. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. 2009 Liver International 29(2): 181-186.

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2011. Mast Cells.