The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 51

63. Why do many mast cell patients gain weight? Why can’t they lose it?

The most common question I get about weight is “Why am I gaining weight when I can barely eat?” Weight gain, or failing to lose weight, is not unusual for mast cell patients. There are a lot of reasons why this happens.

One of the big reasons why mast cell patients gain weight is because mast cells release molecules that cause inflammation. Some of these molecules are known to be linked to obesity when there is too much of them in the body. Mast cells release some of these molecules, like TNF, and IL-6.

Leptin is a hormone released by mast cells that can contribute to obesity. Patients with obesity often have higher than normal levels of leptin in their blood. In these patients, it seems like leptin doesn’t work as well as in others, so their bodies need to make more leptin.

Leptin’s job in the body has long been thought to tell your brain that you are not hungry. More recent research suggests that leptin doesn’t exactly tell your brain that you’re not hungry, and instead tells your brain that your body is starving. The body responds to this “starving” signal very strongly by trying to maintain or gain weight, and to maintain or gain fat stores.

Mast cells live in adipose tissue (fat tissue), often in significant numbers. Leptin level somehow controls the amount of mast cells in adipose tissue (fat tissue) but we are not sure how. Leptin is one of the ways that mast cells tell other cells to become inflamed. It tells cells to make more inflammatory molecules like TNF, IL-2 and IL-6. Mast cells in inflamed spaces can also attract cells from other parts of the body to come and make more inflammation.

Leptin also directly opposes another hormone, ghrelin. Ghrelin is the hormone that tells your brain that you are hungry. When leptin is high, ghrelin is low. Importantly, ghrelin curbs inflammation and tells cells to stop making inflammatory molecules. If leptin is high, ghrelin is not around as much to stop inflammation.

Another way mast cell disease can contribute to weight gain is by swelling. When mast cells are activated, they release molecules that make it easier for fluid in the bloodstream to “fall out” of the bloodstream and get stuck in tissues. When this fluid is stuck in the tissue, your body can’t just pull back into the bloodstream. It takes days for your body to be able to get the fluid out of the tissues and back into a place where it can be used.

Some of the medications used to treat mast cell disease can cause weight gain. H1 antihistamines are probably the drugs most commonly used for mast cell disease. They can cause weight gain. Steroids like prednisone and methylprednisolone cause swelling and weight gain.

Mast cell patients often have difficulty maintaining a normal sleep schedule. Sleep at night is often not restful because mast cells are very active at night. Not sleeping well can cause inflammation, contributing to weight gain.

Exercise can be very tricky for mast cell patients as well. Many patients are deconditioned and out of shape so even low impact exercise can be exhausting or impossible. Mast cell patients often have restrictions on what exercises they can do safely so vigorous exercise to help regulate weight might not be an option.

Mast cell patients often have little control over their diet due to food reactions, reacting to the process of eating, or having other GI conditions like gastroparesis. Safe foods may not be “healthy” and can contribute to weight gain. (Potato chips are a huge part of my diet as a food that is always safe for me.)

I personally struggled with my weight for years as a result of mast cell disease. It has been my experience that reducing inflammation overall is the only way to lose weight. Of course, it is very difficult to reduce inflammation when you have mast cell disease. In my case, I found that a reconditioning program helped me immensely. This is not safe for everyone and you should never start an exercise program without discussing it with the provider that manages your care.


For more detailed reading, please visit the following posts:

Leptin: the obesity hormone released by mast cells
Exercise and mast cell activity
My exercise program for POTS and deconditioning
Deconditioning, orthostatic intolerance, exercise and chronic illness (Part One)
Deconditioning, orthostatic intolerance, exercise and chronic illness (Part Two)
Deconditioning, orthostatic intolerance, exercise and chronic illness (Part Three)
Deconditioning, orthostatic intolerance, exercise and chronic illness (Part Four)
Deconditioning, orthostatic intolerance, exercise and chronic illness (Part Five)
Deconditioning, orthostatic intolerance, exercise and chronic illness (Part Six)
Deconditioning, orthostatic intolerance, exercise and chronic illness (Part Seven)

Reading list: Papers to better understand mast cells and mast cell disease (Part 4)

Mast cells and eosinophils

  • Elishmereni M, Alenius HT, Bradding P, Mizrahi S, Shikotra A, Minai-Fleminger Y, et al. Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro. Allergy 2011;66:376–385.
  • Elishmereni M, Bachelet I, Nissim Ben Efraim AH, Mankuta D, Levi-Schaffer F. Interacting mast cells and eosinophils acquire an enhanced activation state in vitro. Allergy 2013; 68: 171–179.
  • Minai-Fleminger Y, Elishmereni M, Vita F, Soranzo MR, Mankuta D, Zabucchi G et al. Ultrastructural evidence for human mast cell-eosinophil interactions in vitro. Cell Tissue Res 2010; 341: 405–415.
  • Puxeddu I, Ribatti D, Crivellato E, Levi- Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol 2005; 116: 531–536.

Allergic to infections

  • Abraham S. N, St John A. L. (2010). Mast cell-orchestrated immunity to pathogens. 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. Natl. Acad. Sci. U.S.A.1078748–8753
  • 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. Immunol.442087–2094.
  • Gilfillan A. M., Tkaczyk C. (2006). Integrated signalling pathways for mast-cell activation. Rev. Immunol.6218–230.
  • 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. 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. 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.
  • Sandig H, Bulfone-Paus S. TLR signaling in mast cells: common and unique features. Front Immunol. 2012; 3: 185.
  • Varadaradjalou, S., Feger, F., Thieblemont, N., Hamouda, N.B., Pleau, J. M., Dy,M., and Arock, M. (2003). Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. J. Immunol. 33, 899–906.
  • 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. Allergy Clin. Immunol. 120, 452–461.

Interactions with B and T cells

  • Brill, A., Baram, D., Sela, U., Salamon, P., Mekori, Y. A., and Hershkoviz, R. Induction of mast cell interactions with blood vessel wall components by direct contact with intact T cells or T cell membranes in vitro. Exp. Allergy 2004; 34, 1725–1731.
  • Gri, Giorgia, et al. Mast cell: an emerging partner in immune interaction. Front. Immunol., 25 May 2012.

Mast cells in wound healing

  • Douaiher, Jeffrey, et al. Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing Advances in Immunology, Volume 122 (2014): Chapter 6.
  • Westerberg CM, et al. Differentiation of mast cell subpopulations from mouse embryonic stem cells. Journal of Immunological Methods 382 (2012) 160–166.


  • Baek HS, et al. Leptin and urinary leukotriene E4and 9α,11β-prostaglandin F2 release after exercise challenge. Volume 111, Issue 2, August 2013, Pages 112–117
  • Graham P, Kahlson G, Rosengren E. Histamine formation in physical exercise, anoxia and under the influence of adrenaline and related substances. Physiol., 172, 174—188 (1964).
  • Hahn AlG., et al. Histamine reactivity during refractory period after exercise induced asthma. Thorax 1984; 39: 919-923.
  • McNeill RS, Nairn JR, Millar JS, Ingram CG.Exercise-induced asthma. Q J Med 1966; 35: 55-67.
  • Niijima-Yaoita F, et al. Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion. Biol Pharm Bull 2012; 35; 91-97.
  • Schoeffel, Robin E., et al. Multiple exercise and histamine challenge in asthmatic patients. Thorax, 1980, 35, 164-170.
  • Teal S. Hallstrand, Mark W. Moody, Mark M. Wurfel, Lawrence B. Schwartz, William R. Henderson, Jr., and Moira L. Aitken. Inflammatory Basis of Exercise-induced Bronchoconstriction. American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 6 (2005), pp. 679-686.

Circadian rhythm of mast cells

  • Baumann, A., Gonnenwein, S., Bischoff, S.C., Sherman, H., Chapnik, N., Froy, O.,Lorentz, A., 2013. The circadian clock is functional in eosinophils and mast cells. Immunology 4, 465–474.
  • Baumanna A, et al. IgE-dependent activation of human mast cells and fMLP-mediatedactivation of human eosinophils is controlled by the circadian clock. Molecular Immunology 64 (2015) 76–81.
  • Burioka, N., Fukuoka, Y., Koyanagi, S., Miyata, M., Takata, M., Chikumi, H., Takane, H.,Watanabe, M., Endo, M., Sako, T., Suyama, H., Ohdo, S., Shimizu, E., 2010. Asthma: chronopharmacotherapy and the molecular clock. Adv. Drug Deliv. Rev. 9–10,946–955.
  • Cermakian, N., Lange, T., Golombek, D., Sarkar, D., Nakao, A., Shibata, S., Mazzoccoli, G., 2013. Crosstalk between the circadian clock circuitry and the immune system.Chronobiol. Int. 7, 870–888.
  • Nakamura Y, et al. Circadian regulation of allergic reactions by the mast cell clock in mice. J Allergy Clin Immunol 133 (2014) 568-575.
  • Silver, A.C., Arjona, A., Hughes, M.E., Nitabach, M.N., Fikrig, E., 2012. Circadian expres-sion of clock genes in mouse macrophages, dendritic cells, and B cells. Immun. 3, 407–413.
  • Smolensky, M.H., Lemmer, B., Reinberg, A.E., 2007. Chronobiology and chronother-apy of allergic rhinitis and bronchial asthma. Adv. Drug Deliv. Rev. 9–10,852–882.

Microbial effects on mast cell behavior

  • Choi HW, Abraham SN. Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms. Molecular Immunology 63 (2015) 74–79.
  • Choi, H.W., Brooking-Dixon, R., Neupane, S., Lee, C.-J., Miao, E.A., Staats, H.F., Abraham, S.N., 2013. Salmonella typhimurium impedes innate immunity with a mast-cell-suppressing protein tyrosine phosphatase, SptP. Immunity 39,1108–1120.
  • Cornelis, G.R., 2002. Yersinia type III secretion: send in the effectors. Cell Biol. 158, 401–408.
  • Forsythe, P., Wang, B., Khambati, I., Kunze, W.A., 2012. Systemic effects of ingested Lactobacillus rhamnosus: inhibition of mast cell membrane potassium (IKCa)current and degranulation. PLoS One 7, e41234.
  • Harata, G., He, F., Takahashi, K., Hosono, A., Kawase, M., Kubota, A., Hiramatsu, M.,Kaminogawa, S., 2010. Bifidobacterium suppresses IgE-mediated degranulationof rat basophilic leukemia (RBL-2H3) cells. Microbiol. Immunol. 54, 54–57.
  • Magerl, M., Lammel, V., Siebenhaar, F., Zuberbier, T., Metz, M., Maurer, M., 2008. Non-pathogenic commensal Escherichia coli bacteria can inhibit degranulation of mast cells. Exp. Dermatol. 17, 427–435.
  • Melendez, A.J., Harnett, M.M., Pushparaj, P.N., Wong, W.S., Tay, H.K., McSharry, C.P.,Harnett, W., 2007. Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat. Med. 13, 1375–1381.
  • Niide, O., Suzuki, Y., Yoshimaru, T., Inoue, T., Takayama, T., Ra, C., 2006. Fungal metabolite gliotoxin blocks mast cell activation by a calcium- and superoxide-dependent mechanism: implications for immunosuppressive activities. Clin.Immunol. 118, 108–116.
  • Oksaharju, A., Kankainen, M., Kekkonen, R.A., Lindstedt, K.A., Kovanen, P.T., Korpela,R., Miettinen, M., 2011. Probiotic Lactobacillus rhamnosus downregulates FCER1and HRH4 expression in human mast cells. World J. Gastroenterol. 17, 750–759.
  • Wesolowski, J., Paumet, F., 2011. The impact of bacterial infection on mast celldegranulation. Immunol. Res. 51, 215–226.

My exercise program for POTS and deconditioning

I designed the following schedule for myself after being medically cleared to return to exercise following surgery. This routine is not appropriate for everyone. Please speak with your medical provider regarding safe ways to exercise.

I put together this routine for myself by integrating POTS/dysautonomia exercise programs and my own personal exercise history. Even on my most miserable days, I walk for 20-30 minutes, so walking is something that I can trust to not raise my heart rate. I also have been practicing vinyasa style yoga for over fifteen years and started with very easy seated poses and progressed to more fluid sequences (Sun Salutation A 3-5x, Sun Salutation B 3x, followed by whatever sequences I felt were reasonable for that day.)

For the first few weeks, I timed my exercise for about an hour after taking antihistamines. For weeks 1-3, I performed all of my allotted exercise for the day consecutively over about an hour. For weeks 4-8, walking was often broken up over the course of the day as this included walking I did as part of my commute. My first walk of the day occurs within an hour of taking my morning medications and I take meds about an hour before leaving work for the day to cover my commute home.

Slow walking: about 2.5-3 miles/hour
Moderate walking: about 3-3.5 miles/hour

For seated cardio, I just looked around online for some seated cardio that I could do at home. I found a few routines.

For standing cardio, I did various things like jumping jacks and high knees. I usually incorporated bodyweight exercises that I could modify, like squats and planks.

Walking was all done outside. Some was done at night and some during the day. I tried to limit walking during the middle of the day to the extent that it was possible because heat and sunlight trigger me. All other exercises were done in my air conditioned apartment.

If I felt like I needed a break while exercising, I took a break. So ten minutes of cardio does not always represent ten consecutive minutes, but rather a total of ten minutes performing cardio exercise.

As I added in more exercise, I increased to exercising four days a week, which means that sometimes I exercise twice in one day. Walking is also split up over the course of the day, as I previously mentioned.

Week One:

Three days:
Twenty minutes of slow walking
Ten minutes seated cardio
Twenty minutes stretching/seated yoga
Ten minutes slow walking

Week Two:

Three days:
Thirty minutes of slow/moderate walking
Ten minutes seated cardio
Ten minutes yoga
Ten minutes stretching

Week Three:

Three days:
Forty minutes of moderate walking
Twenty minutes yoga
Ten minutes stretching

One day:
Sixty minutes of walking

Week Four:

Two days:
Fifty minutes of moderate walking
Twenty minutes of yoga

One day:
Fifty minutes of moderate walking

Week Five:

Two days:
Fifty minutes of moderate walking
Twenty minutes of yoga

One day:
Fifty minutes of moderate walking
Ten minutes of standing cardio

One day:
Sixty minutes of moderate walking

Week Six:

Two days:
Sixty minutes of moderate walking
Twenty minutes of yoga

Two days:
Fifty minutes of moderate walking
Ten minutes of standing cardio

Week Seven:

Two days:
Sixty minutes of moderate walking
Twenty minutes of yoga

Two days:
Fifty minutes of moderate walking
Fifteen minutes of standing cardio

Week Eight:

Two days:
Fifteen-twenty minutes of standing cardio
Twenty minutes of yoga

Three days:
Sixty minutes of moderate walking


Edited on 29 Jan 2017 to include weeks 9-12 of this program:

Week Nine:

Two days:
Twenty minutes of standing cardio
Thirty minutes of yoga (intermediate)

Three days:
Sixty minutes of moderate walking

Week Ten:

Three days:
Twenty minutes of standing cardio
Forty minutes of yoga (intermediate)

Three days:
Sixty minutes of moderate walking

Week Eleven:

Three days:
Fifty minutes of yoga (intermediate/advanced, pace moderate/fast)

Three days:
Sixty minutes of moderate walking

Week Twelve:

Three days:
Sixty minutes of yoga (intermediate/advanced, pace moderate/fast)

Three days:
Sixty minutes of moderate walking

Independence Day

I live my life as a series of wagers. A lot of these wagers involve my health. I bet that I can fly if I take enough steroids. I bet that I will get better if I get an ostomy. I bet that I will be more stable if I use IV hydration. I bet that taking this med or that will make me less tired. Sometimes I win. Sometimes I don’t.

The last 18 months of my life have all been one large scale bet. It has been many months of moving the pieces around and trying to shove them into place. It has been emotional and stressful and scary.

I slept through the four weeks following my surgery. I did some other things too, but mostly I slept. One day while I was resting in bed, it occurred to me that all of the strength and stamina I had lost was perhaps for the best. There are few opportunities to reset your body and this was one of them. I wasn’t reacting because I was heavily medicating and resting most of the time. I realized that this might be an opportunity to rebuild my body in a calculated way.

Once I was cleared by my surgeon to exercise, I started an exercise program designed for POTS patients. It was pretty detailed (I’ll do a separate post about this) but involved cardio exercise 3-4 days a week. I haven’t been able to do cardio in years. But I figured it was worth a shot.

The first two weeks were brutally hard. Then it got easier. I am now on the sixth week of a twelve week program. For the first time in many years, I can do cardio (with premedication in a controlled environment) without having a reaction.

I went back to work last week. I took the train to and from work on Monday, Wednesday and Thursday, which also involves about a mile and a half of walking each day. It was pouring torrentially on Wednesday and hot as hell on Thursday. I was exhausted when I got home but I managed to get through each day without napping. I slept every night last week. Getting myself to and from work is a level of independence I have not achieved in a year.

I very rarely drive anymore because I can’t use some of my medications if I need to drive and I have been so reactive that that might have been dangerous. But I made a huge wager on Saturday: I drove myself an hour away to New Hampshire to celebrate the Fourth of July with my friends and nieces. I stayed overnight and went swimming today, deaccessing and reaccessing my port. I drove myself home after being in cold water and direct sunlight for over an hour, stopping at Whole Foods and doing my grocery shopping on the way. I cleaned my apartment, did laundry, made lunch for tomorrow, ironed my work clothes, and watched Shark Week. I did all these things without any help.

The Fourth of July is Independence Day in the US. As I watched the fireworks, it felt like I was celebrating my own personal Day of Independence. I don’t know how long this will last.  But I got this one great week and this one Fourth of July.  And maybe I’ll get more.

Deconditioning, orthostatic intolerance, exercise and chronic illness – Part 7

A number of studies have investigated whether loading with intravenous hydration solutions (saline, etc) or with a volume expander such as dextran can ameliorate symptoms associated with deconditioning. These studies have found that volume expansion (also called fluid or volume loading) can improve a number of symptoms in deconditioned patients, but does not improve exercise capacity. Multiple studies have found the best effects from intravenous saline in conjunction with exercise.

Shibata investigated whether orthostatic intolerance could be mitigated following bed rest with exercise and/or fluid loading (Shibata 2010). This study found that OI could be dextran solution (IV fluids) given after twenty days of bed rest was insufficient to control OI symptoms, but that it was successful when used in conjunction with a daily exercise program. This finding was important, as it indicated that low blood volume was not the exclusive factor in orthostatic intolerance.

Figueroa et al looked at the relationship between blood volume and exercise capacity in POTS patients (Figueroa 2014). They found that acute volume loading with IV saline reduces heart rate and improves orthostatic tolerance and other symptoms in POTS patients. Importantly, IV saline significantly increased the stroke volume, cardiac output and reduced systemic vascular resistance. However, IV saline did not affect peak exercise capacity or improve cardiovascular markers during exercise. So while IV saline does help symptoms in these deconditioned patients, it does not improve exercise capacity. The author notes that for this purpose, acute infusion may not be sufficient and may need to undergone chronically to see benefits on exercise physiology.

Whole body heating is known to increase cardiac output, constrict the blood vessels in the abdominal cavities, increase sympathetic nerve activity in the muscles and decrease vascular resistance in the skin. Taken together, these factors stress the regulatory mechanism of the cardiovascular system. One study (Keller 2009) found that acute expansion of blood volume (with dextran) completely mitigated the impact of heat stress on orthostatic tolerance. In short, receiving an infusion that increased the blood volume allowed the cardiovascular system to function properly in the face of a known stressor.

One study looked at the effect of fluid loading on orthostatic intolerance and blood flow in the brain (Jeong 2012). They found that following bed rest, volume loading alone prevented larger reductions in cerebral blood flow, but did not prevent orthostatic intolerance. Exercise and volume loading prevented orthostatic intolerance but did not affect cerebral blood flow. Importantly, aerobic or resistance exercise before bed rest did not prevent development of decompensation.

A 2000 paper notes that POTS symptom scores improved significantly following administration of IV saline (Gordon 2000). Additionally, a 2013 study evaluated the frequency and characterization of “brain fog”, a common term for the cognitive deficits associated with this (and other) conditions (Joyner 2013). 86% (56/66) of patients reported that IV saline was the most effective treatment for brain fog.

In summary, bolus IV fluids or volume expanders have been found to improve a number of symptoms in deconditioned patients, although they have not been found to improve exercise capacity. For this metric, a graded exercise program is recommended. 

(Author’s note: I have recently been made aware that the data supporting use of graded exercise for chronic fatigue patients was hugely flawed. I retract this statement at this time. For details on this topic, please refer to this Lancet article:

A 2008 paper compared POTS and deconditioning (Joyner 2008). The author pointed out that a number of parallels existed between the physiological changes seen in POTS patients and those seen in deconditioned patients. Additionally, he made note of the parallels between POTS, chronic fatigue syndrome and fibromyalgia and the fact that exercise training had seen benefits in all of them. Given the significant relationship between mast cell disease and POTS, and the large overlap in CFS, fibromyalgia and mast cell populations, it is a comfortable assumption that an effective treatment modality for CFS, POTS and fibromyalgia may also be effective for mast cell disease. It is my belief that this is the basis for the frequently discussed finding of mast cell patients that intravenous fluids ameliorate a number of symptoms.

Furthermore, there are special considerations for mast cell disease that make intravenous fluids likely to cause a positive change in symptom profile. The first is that mast cell degranulation can induce systemic effects on arterial tone, hypotension and vasodilation (Willingham 2009). The next is that hypotension is characteristic of systemic mastocytosis, and that hypotension and syncope may occur due to cerebral hypoperfusion (Ozdemir 2010). Lastly, it is well known that mast cell mediators, including histamine, serotonin and tryptase, can induce capillary leakage leading leading to edema, and that they can increase vascular permeability (He 1997). Taken together, these points indicate that a mast cell patient may lose volume from the bloodstream into the surrounding tissues, which can exacerbate an already existing tendency toward hypotension, in turn made worse by orthostatic intolerance.

Fluid loading in the form of intravenous fluids may decrease symptoms in mast cell patients due to deconditioning, orthostatic intolerance and the capillary leakage often seen as a result of mast cell disease, which is especially present following mast cell attacks and anaphylaxis.



Gordon VM., et al. Hemodynamic and symptomatic effects of acute interventions on tilt in patients with postural tachycardia syndrome. Clin Auton Res. 2000 Feb; 10(1): 29-33.

Ross, Amanda J., et al. What is brain fog? An evaluation of the symptom in postural tachycardia syndrome. Clin Auton Res 2013 Dec; 23(6): 305-311.

Raj, Satish R., et al. Postural orthostatic tachycardia syndrome (POTS). Circulation 2013; 127: 2336-2342.

Rocío A. Figueroa, et al. Acute volume loading and exercise capacity in postural tachycardia syndrome. J Appl Physiol 117:663-668, 2014.

He, Shaoheng, Walls, Andrew F. Mast cell activation may be all that is sufficient and necessary for the rapid development of microvascular leakage and tissue edema. European Journal of Pharmacology 1997; 328(1): 89-97.

Ozdemir, D., et al. Hypotension, syncope and fever in systemic mastocytosis without skin infiltration and rapid response to corticosteroid and cyclosporine: a case report. Case Reports in Medicine, Volume 2010 (2010), Article ID 782595.

Willingham DL, et al. Unexplained and prolonged perioperative hypotension after orthotopic liver transplantation: undiagnosed systemic mastocytosis. Liver Transpl 2009 Jul; 15(7): 701-8.

Keller, David M., et al. Acute volume expansion preserves orthostatic tolerance during whole body heat stress in humans. J Physiol 2009 Mar; 587(5): 1131-1139.

Sung-Moon Jeong , Shigeki Shibata , Benjamin D. Levine , Rong Zhang. Exercise plus volume loading prevents orthostatic intolerance but not reduction in cerebral blood flow velocity after bed rest. American Journal of Physiology – Heart and Circulatory Physiology 2012 Vol. 302 no. 2.

Shizue Masuki , John H. Eisenach , William G. Schrage , Christopher P. Johnson , Niki M. Dietz , Brad W. Wilkins , Paola Sandroni , Phillip A. Low , Michael J. Joyner. Reduced stroke volume during exercise in postural tachycardia syndrome. Journal of Applied Physiology 2007 Vol. 103 no. 4, 1128-1135.






Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 6

Exercise can be very effective in treating deconditioning due to orthostatic intolerance or other conditions. Exercise can exacerbate symptoms in deconditioned patients even when it is mild, and this effect will be more pronounced if exercising in hot weather or after eating. Recumbent exercise, rather upright, is ideal for deconditioned patients at the beginning of exercise regimens, as being upright more stress on the body.

There are some physical maneuvers that can be helpful in avoiding OI episodes or in managing them when they do occur.   A sustained hand grip will activate the sympathetic nervous system and raise blood pressure for a short time. This can be helpful when changing position or following triggering activities, such as eating a meal or exercising. Leg crossing while tensing muscles can also prevent blood from pooling in the leg veins. This is recommended when an OI episode first occurs, and for vasovagal syncope patients to prevent fainting.

One study regimen prescribed POTS patients to engage in recumbent exercise 2-4 times a week for 30-45 minute sessions. In this study, they attempted to keep heart rate at 75-85% of maximum heart rate. As patients continued and became more fit, upright exercise was added in slowly in the second or third week. The length of training sessions increased and sessions of maximum intensity was added gradually until there were two maximum sessions per week. Weight lifting started once a week as a 15-20 minute session and increased to twice weekly 30-40 minute sessions. At the end, patients were exercising 5-6 hours/week. The duration of this study was twelve weeks.

Of the 29 patients who completed this study, a number of cardiovascular markers were improved. Blood volume and plasma volume were both expanded. The peak oxygen uptake during exercise, usually low for POTS patients, was increased by 11%. The muscle in the left ventricle of the heart, often smaller than usual in POTS patients, increased by 8%. Both laying down and standing heart rates decreasing significantly. Quality of life improved significantly and at the conclusion, almost half of the patients who completed the training no longer met the criteria for POTS.

Another study had POTS patients begin exercising twice a week in recumbent exercise, such as rowing or swimming, for 30-45 minutes. They increased to four times per week. After three months, plasma and blood volumes were both increased, as well as total hemoglobin mass and red blood cell volume. Systolic and diastolic pressures were lower while standing. Standing heart rate was lower and the amount of blood pumped out of the heart was stable.

Multiple papers have noted that OI patients are motivated to exercise, but often exert themselves too much in the beginning and trigger symptoms that make it difficult to continue. Going slowly and building up your tolerance is critical here. It is the factor that will make this successful. As an example, when I was very POTSy last year after several days of bed rest, I was advised that I could only stand for 10 minutes a day for an entire week. I could increase by ten minutes every week until I got to sixty, at which point I could resume normal activity. It was incredibly frustrating and drove me crazy, but I was able to get my orthostatic symptoms under control. Gradually increasing activity for OI patients is tried and true.

For severely disabled patients, it may not be practical to begin with recumbent aerobic exercises. If this is the case, gentle stretching and very low impact moves are good to start.

Following this, short workouts preceded by 5-10 minutes of stretching can be added. Target heart rate of 75-80% has been cited as desirable in some publications. Of utmost importance is the use of recumbent exercises, like rowing, swimming or recumbent cycling. Start slow. Dysautonomia International has a great breakdown on their site for how long you should workout at this stage.

Following several weeks of success, normal weekends can be introduced. Some patients are able to recover significant capability, running marathons and so on. It is recommended that POTS patients who are significantly conditioned exercise for at least 45 minutes three times a week.

While OI is a prime example of deconditioning as so many of its patients are deconditioned (95% of POTS patients and 91% of OI patients in one study), it is not the only condition associated with deconditioning that can be significantly improved with exercise.

In various studies with chronic fatigue syndrome patients, 60-84% said they felt better or much better after a graded exercise program. A study with fibromyalgia implemented three times a week workouts of sixty minutes, which included 10 minutes of slow walking, 20 minutes of aerobic exercise at 60-70% max heart rate, 20 minutes stretching and strength training, and 10 minutes cooling down. This program was highly successful for a number of patients.

Given the variety of illnesses which produce secondary deconditioning, and the success achieved by their patient populations with graded exercise, it is reasonable to assume that graded exercise may provide conditioning benefits to the mast cell population. Mast cell patients have the addition concerns that mast cells can be mechanically degranulated by the motions associated with vigorous exercise and that heat and sweating may be triggering, so exercise should be undertaken carefully and never alone. Some patients find utility in premedicating with H1 and H2 antihistamines before exercising. Please consult with your healthcare provider prior to beginning an exercise regimen.



De Lorenzo, H. Xiao, M. Mukherjee, J. Harcup, S. Suleiman, Z. Kadziola and V.V. Kakkar. Chronic fatigue syndrome: physical and cardiovascular deconditioning. Q J Med 1998; 91:475–481.

Hasser, E. M. And Moffitt, J. A. (2001), Regulation of Sympathetic Nervous System Function after Cardiovascular Deconditioning. Annals of the New York Academy of Sciences, 940: 454–468.

Mathias, C. J. et al. Postural tachycardia syndrome – current experience and concepts. Nat. Rev. Neurol. 8, 22–34 (2012).

Parsaik A., et al. Deconditioning in patients with orthostatic intolerance. Neurology 2012; 79; 1435.

Benarroch, Eduardo E. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 2012 Dec; 87(12): 1214-1225.

Shizue Masuki , John H. Eisenach , William G. Schrage , Christopher P. Johnson , Niki M. Dietz , Brad W. Wilkins , Paola Sandroni , Phillip A. Low , Michael J. Joyner. Reduced stroke volume during exercise in postural tachycardia syndrome. Journal of Applied Physiology Published 1 October 2007 Vol. 103 no. 4, 1128-1135.

Sung-Moon Jeong , Gyu-Sam Hwang , Seon-Ok Kim , Benjamin D. Levine , Rong Zhang. Dynamic cerebral autoregulation after bed rest: effects of volume loading and exercise countermeasures. Journal of Applied Physiology 2014 Vol. 116 no. 1, 24-31.




Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4

Syncope, also called fainting, is the loss of consciousness caused by temporary loss of blood supply to the brain, followed by complete recovery. About 40% of people will faint in their lifetime and half of them will first faint as teenagers, around the age of 15. Fainting can be caused by orthostatic hypotension. Otherwise, it can occur for cardiac or neurologic reasons (also called reflex syncope). One type of reflex syncope is vagovagal syncope, which can be further divided into postural syncope (fainting upon standing) and emotional or phobic syncope (fainting due to unpleasant psychological stimuli).

Vagovagal syncope has been attributed to several things, but none have been definitively proven. Some patients have decreased presence of enzymes that mediate blood pressure, like norepinephrine transportase (NET). Some have insufficient circulation in the abdominal cavity. As vasovagal syncope is often preceded by lightheadedness, sweating, weakness, nausea and visual disturbances, it can be difficult to distinguish between VVS and POTS. However, VVS patients often go long periods without OI symptoms, which only occur immediately before syncope.   Postural syncope and POTS are also associated with increased rate and depth of breathing in order to meet oxygen needs during these episodes.

Ingestion of 16 ounces of water in five minutes is known to effectively treat OI episodes of all types. It begins to have effect in about twenty minutes. It is important that this water not have solutes; that is to say, it should be pure water. Effects can last for hours.

There are a number of precipitating factors that can induce OI symptoms in susceptible patients. Avoidance is a key treatment modality. These factors include large meals, sudden postural changes, laying down for extended periods of time, environmental heat, alcohol, vasodilators* and sympathomimetic drugs, such as methylphenidate. (*It is worth noting that mast cell disease is inherently vasodilatory).

For both orthostatic hypotension and neurogenic POTS patients, physical maneuvers and compression garments can decrease venous pooling of blood. Increasing both salt and water intake can be helpful to expand plasma volume; 1.5-2L is recommended for adults.

Medications that retain salt and water, such as fludrocortisone, may be tried as well. Pressor drugs with short half lives, such as midodrine and pyridostigmine, are also used in these patients. Droxidopa is used outside of the US. Other meds, such as clonidine, also see some utility. Exercise is also encouraged as a treatment option (will be detailed in a follow up post).

HyperPOTS is often treated with beta blockers. (WARNING: beta blockers interfere with the action of epinephrine and should be used cautiously in mast cell patients). Angiotensin receptor blockers like Cozaar have been used, as has droxidopa. Exercise is likewise suggested for treatment of this patient group.

Water ingestion is recommended for patients with vasovagal syncope. Additionally, physical maneuvers are advised upon the onset of OI symptoms.



Stewart, Julian M. Update on the theory and management of orthostatic intolerance and related syndromes in adolescents and children. Expert Rev Cardiovasc Ther 2012 November; 10(11): 1387-1399.

Benarroch, Eduardo E. Postural tachycardia syndrome: a heterogenous and multifactorial disorder. Mayo Clinic Proceedings 2012; 87(12): 1214-1225.


Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1

Deconditioning (also called cardiovascular deconditioning) is the acclimation of the body to a less strenuous environment and the decreased ability to function properly under normal conditions. This basically means that when you have less physical stress on the body for a certain period of time, like seen in bed rest, the body adapts to that level of functioning, so when you want to engage again in normal physical activities, it is difficult for your body. Deconditioning makes multiple systems of your body less functional.

Bed rest is the typical situation associated with deconditioning. Patients on bed rest lose muscle mass and strength rapidly.  1-3% of muscle strength is lost per day, with 10-20% decrease in a week’s time. If completely immobilized for 3-5 weeks, a patient can lose up to 50% of their strength. Loss of muscle mass is also a problem. Upper legs can lose 3% mass within a week of bed rest. The lower back and weight bearing muscles in the legs are most affected by loss of mass.

Within 24 hours of bed rest, your cardiovascular system is changing. In this time, your blood volume decreases 5%. In less than a week, 10% is lost; in two weeks, 20%. Resting heart rate also increases 4-15 bpm within the first month of bed rest. Laying down for so long means that blood that is normally in the lower part of your body is moved to the trunk. This causes excretion of water and salt, resulting in less plasma and blood volume.

In healthy controls, when you change position, your body rapidly moves fluid from one part of the body to others. This phenomenon is called fluid shifting. Normally, when moving from a laying position to standing, 500-700 ml of blood are moved from the trunk to the legs. This movement of fluid is called “functional hemorrhage”. Special nerve clusters called baroreceptors (which measure pressure in the blood vessels) tell the nervous system that there is less blood in the chest.   Your body then increases the heart rate, the force with which your heart beats, tightens up vessels so that they are less “leaky” and tells your body not to make urine temporarily. All of these functions allow your body to keep a normal blood pressure and adequate blood supply despite this large movement of fluid.

In healthy controls, when you lay down after standing, the reverse happens. 500-700 ml of fluid is rapidly transferred from the lower body to the trunk. This is called a “central shift”. This increase in fluid in the chest results in the veins returning more blood to the heart, increasing blood pressure. When the baroreceptors feel more pressure than usual from this added fluid, the heart rate and force with which the heart beats decrease, the vessels are relaxed so that fluids can move out of them more freely and your body begins to make urine again.

When you are deconditioned, your body does not make these changes correctly when you change position. The hallmark of deconditioning is reduced orthostatic tolerance. This means that when you change position, your body does not compensate correctly to maintain necessary blood pressure and adequate blood supply to the brain. Deconditioned patients often do not have sufficient blood volume to maintain blood pressure when standing. When they stand, their heart pumps out less blood than normal, so the heart starts beating faster to compensate. When it beats too fast, it is called tachycardia.

In addition to inability to maintain blood pressure correctly when changing positions, deconditioned patients also exhibit decreased blood volume pumped out by the heart, atrophy of heart muscle and decreased maximum oxygen consumption. These patients often have other forms of vascular dysfunction, diminished neurologic reflexes and reduced ability to exercise. A number of other systems are affected by deconditioning.

Though prolonged bed rest is the model with which deconditioning is most often associated, there is significant evidence that chronically ill patients may often be deconditioned, including those with chronic lower back pain, chronic fatigue syndrome, and rheumatoid arthritis.


Munsterman et al. Are persons with rheumatoid arthritis deconditioned? A review of physical activity and aerobic capacity. BMC Musculoskeletal Disorders 2012, 13:202

Eric J. Bousema, Jeanine A. Verbunt, Henk A.M. Seelen, Johan W.S. Vlaeyen, J. Andre Knottnerus. Disuse and physical deconditioning in the first year after the onset of back pain. Pain 130 (2007) 279–286.

De Lorenzo, H. Xiao, M. Mukherjee, J. Harcup, S. Suleiman, Z. Kadziola and V.V. Kakkar. Chronic fatigue syndrome: physical and cardiovascular deconditioning. Q J Med 1998; 91:475–481.

Hasser, E. M. And Moffitt, J. A. (2001), Regulation of Sympathetic Nervous System Function after Cardiovascular Deconditioning. Annals of the New York Academy of Sciences, 940: 454–468.

Exercise and mast cell activity

Research on exercise induced bronchoconstriction represents a large body of work through which we can draw conclusions about mast cell behavior as affected by exercise.

Exercise has been found in a number of studies to induce mast cell degranulation and release of de novo (newly made) mediators. One study found that levels of histamine, tryptase and leukotrienes were increased following exercise in sputum of people with exercise induced bronchoconstriction. This same study found that in these patients, prostaglandin E2 and thromboxane B2 was decreased in sputum. Treating with montelukast and loratadine suppressed release of leukotrienes and histamine during exercise.

One important area of research is the interface between being asthmatic and being obese. Adipose tissue is known to release inflammatory molecules called adipokines. In particular, the adipokine leptin has been studied for its role in bronchoconstriction following exercise. Leptin (I did a previous post on leptin, which is also called the obesity hormone) enhances airway reactivity, airway inflammation and allergic response. It can also enhance leukotriene production. This last fact is interesting because obese asthmatics are less likely to respond to inhaled corticosteroids when compared to lean asthmatics, but both respond similarly to anti-leukotriene medications like montelukast.

LTE4 was found to be significantly higher in the urine of both obese and lean asthmatics following exercise. It was not increased in either obese non-asthmatics or healthy controls. Additionally, the level of LTE4 was significantly higher in obese asthmatics compared to lean asthmatics. In this same study, urinary 9a, 11b-PGF2 was elevated in both lean and obese asthmatics, but not in obese or healthy controls. The 9a, 11b-PGF2 level was also higher in obese asthmatics than lean asthmatics. The elevated LTE4 and 9a, 11b-PGF2 were found in urine testing rather than in sputum, indicating that these chemicals did not stay local to the lungs and airway.

It is thought that the high levels of leptin found in asthmatics drive the manufacture and release of leukotrienes and prostaglandins from mast cells, epithelial cells or eosinophils during exercise. Though the data are stacking up to look like this is the case, there has not yet been a definitive causal link established.



Teal S. Hallstrand, Mark W. Moody, Mark M. Wurfel, Lawrence B. Schwartz, William R. Henderson, Jr., and Moira L. Aitken. Inflammatory Basis of Exercise-induced Bronchoconstriction. American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 6 (2005), pp. 679-686.

Hey-Sung Baek, et al. Leptin and urinary leukotriene E4 and 9α,11β-prostaglandin F2 release after exercise challenge. Volume 111, Issue 2, August 2013, Pages 112–117


Histamine depletion in exercise

A long known and often repeated finding is that regular exercise can be protective against asthma. This finding was published in 1966 by a group that found the airways of asthmatics grew progressively less reactive following intervals of exercise. This finding was confirmed by several studies that followed. At the time, the reason why exercise protected against reactive airways was unclear, but an early hypothesis was that mediators were depleted after the initial round of exercise and that time was required to restore them.

In the 1980’s, there was a wave of research around the role of histamine in airway reactivity of asthmatics. There were a few competing theories at this point for why asthmatics became less reactive following exercise: depletion of mediators, mainly histamine from mast cells; that bronchial smooth muscle became less responsive to stimulation by histamine via the H1 receptor; and that release of catecholamines (such as epinephrine) by exercise suppresses bronchoconstriction. A number of studies made relevant findings.

Histamine is known to be released in the lungs due to exercise. It is also known to become depleted and quickly metabolized. When exposed to histamine, asthmatics recover quickly from the ensuing bronchoconstriction. Some asthmatic patients show an increase in plasma histamine during exercise.

Plasma epinephrine does not rise in asthma patients as a result of exercise, or at the very least is metabolized almost immediately, and thus is unlikely to be protective. Bronchial smooth muscle was not found to become less responsive to histamine. This was demonstrated in a study that compared repeated inhalation of histamine (such as might be induced by exercise) with actual repeated exercise. This study found that repeated exercise diminished airway reactivity, while repeated inhalation of histamine did not.

Another report indicated that inhalation of cromolyn before exercise can prevent or mitigate exercise induced asthma in most patients. Administration of H1 inverse agonists was found to offer similar protection.

A more recent study (2012) looked at the role of histamine in fatigue from exercise. Histamine is now known to be involved in regulation of oxygen/carbon dioxide exchange, which is important in exercise. In mice that were persistently exercised, the level of histidine decarboxylase was increased. HDC is the enzyme that makes and immediately releases histamine in response to an immediate need. This is different from degranulation, in which histamine is made ahead of time and stored inside the cell until needed.

This study found that treating the mice with an H1 antihistamine, H2 antihistamine, or HDC inhibitor decreased endurance in the mice. Mice deficient in HDC or H1 receptors also had less endurance. This means that histamine is partly responsible for inducing tolerance to exercise and that blocking action of histamine causes fatigue to set in more quickly.

Treatment with fexofenadine, an H1 antihistamine, decreased levels of nitric oxide and glycogen in the muscles of exercised mice. Taken together, these findings mean that histamine protects against fatigue from exercise; that this effect is achieved via H1 receptors and production of nitric oxide; and that at least some of this histamine is provided by immediate production and release of histamine via HDC. This means that your body does not simply release its histamine stores in response to exercise; it makes it on the fly so as not to exhaust its supply.



Hahn, Allan G., et al. Histamine reactivity during refractory period after exercise induced asthma. Thorax 1984; 39: 919-923.

Niijima-Yaoita, Fukie, et al. Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion. Biol Pharm Bull 2012; 35; 91-97.

Schoeffel, Robin E., et al. Multiple exercise and histamine challenge in asthmatic patients. Thorax, 1980, 35, 164-170.

Graham P, Kahlson G, Rosengren E. Histamine formation in physical exercise, anoxia and under the influence of adrenaline and related substances. J. Physiol., 172, 174—188 (1964).

McNeill RS, Nairn JR, Millar JS, Ingram CG.Exercise-induced asthma. Q J Med 1966; 35: 55-67.