Skip to content

Activating the complement system: Classical, alternative and lectin pathways

The complement system is part of the innate immune system, meaning it does not “learn” over time by being exposed to organisms, and its behavior is the same throughout life. This system is made up of many small proteins that are manufactured in the liver and then released into the bloodstream. Importantly, these proteins are in an inactive state when they move out of the liver. To be active, these proteins have to be “cleaved” or have pieces of the molecule cut off. This is done by other proteins when specific signals are detected.

The complement system undergoes large scale amplification, meaning many, many proteins can be cleaved to fight infection from only one small signal. Once there are many complement proteins to help, they help to kill microbes by building a tunnel through the cell membrane. This tunnel is called the membrane attack complex (MAC).

There are three methods for activating the complement system, all of which involve several steps and several molecules.  It is crucial that these complements are present in the correct ratio or it can contribute to inflammation and disease.

The classical pathway is activated in one of three ways:

  1. Activation:
  • An antibody binds to the outside of microbe. This can be done by certain types of IgG (but not IgG4) or IgM.
  • The enzyme C1 can also bind to the surface of some microbes.
  • C-reactive protein can also activate the classical system by binding to some microbial products.
  1. In the blood, C1 is actually made up of three small parts called subunits: C1q, C1r and C1s. The C1q binds to the antibody on the surface of the microbe. This activates the subunits.
  2. C1s cleaves C4 into two pieces. C4b binds to the cell surface of the microbes. C4a has no function here and is broken down after being released.
  3. C1s cleaves C2 into two pieces. C2b binds to C4b, which is bound to the cell surface. C2a has no function here and is broken down after being released.
  4. When C4b and C2b are bound together, they are called C3 convertase and they perform the special function of cleaves C3. C3 is cleaved into two pieces.
  5. C3b binds to various places on the cell surface. Macrophages and neutrophils (immune cells) can bind to C3b. When macrophages bind to C3b, it may then phagocytose (or eat) the microbe. C3b can also bind to C5, which allows it to be cleaved by C3/C5 convertase.
  6. C3a is an anaphylatoxin. (I have written a previous detailed post on this). It can trigger basophils and mast cells to degranulate.
  7. C5 is cleaved by C3/C5 convertase. This release C5a and C5b.
  8. C5a is a very strong anaphylatoxin and also attracts neutrophils to fight infections.
  9. C5b is the anchor for the membrane attack complex. C6, C7, C8 and several molecules of C9 form a long line on molecules that pokes a whole in the membrane of the microbe. If the membrane is broken, water will rush into the cell and the cell will not function correctly. This results in cell death.

The alternative pathway is activated as follows:

  1. C3 can turn itself into the molecule C3b. This is spontaneous and does not require any other molecules. C3b is short lived under normal circumstances.
  2. If a microbe is nearby, C3b will bind to a molecule on the microbial surface called Factor B.
  3. C3b and Factor B bound together are a different kind of C3 convertase than the one described for classical pathway. This C3 convertase cleaves other molecules.
  4. C3b-Factor B, a C3 convertase, cleaves a molecule of C3.
  5. The liberated molecule of C3b binds to C3b-Factor B-C3b. This is a C5 convertase, which starts the membrane attack complex.
  6. While the MAC is being made, this C5 convertase is still cleaving C3 to release large amounts of C3b.

The lectin pathway is activated as follows:

  1. MBL and ficolin bind to microbial surfaces.
  2. This activates the molecule MASP-2.
  3. MASP-2 cleaves C4 and C2, forming a grouping of molecules called the terminal complement complex (TCC).
  4. C1s cleaves C2 into two pieces. C2b binds to C4b, which is bound to the cell surface. C2a has no function here and is broken down after being released.
  5. When C4b and C2b are bound together, they are called C3 convertase and they perform the special function of cleaves C3. C3 is cleaved into two pieces.
  6. C3b binds to various places on the cell surface. Macrophages and neutrophils (immune cells) can bind to C3b. When macrophages bind to C3b, it may then phagocytose (or eat) the microbe. C3b can also bind to C5, which allows it to be cleaved by C3/C5 convertase.
  7. C3a is an anaphylatoxin. (I have written a previous detailed post on this). It can trigger basophils and mast cells to degranulate.
  8. C5 is cleaved by C3/C5 convertase. This release C5a and C5b.
  9. C5a is a very strong anaphylatoxin and also attracts neutrophils to fight infections.
  10. C5b is the anchor for the membrane attack complex. C6, C7, C8 and several molecules of C9 form a long line on molecules that pokes a whole in the membrane of the microbe. If the membrane is broken, water will rush into the cell and the cell will not function correctly. This results in cell death.

 

Some molecules control the complement system so that the amplification does not cause problems.

  • Factor H controls the alternative pathway. It helps to degrade the C3b-Factor B-C3b complex.
  • Factor I converts C3b to an inactive form.
  • C1INH (C1 inhibitor) binds to activated C1r and C1s, making them inactive. This happens quickly, so there is only a brief time before C1INH binds to C1r or C1s during which they can cleave C4 and C2.

 

 

 

Master table of de novo mast cell mediators

 

Mediator Symptoms Pathophysiology
b-FGF (basic fibroblast growth factor) Angiogenesis, proliferation, wound healing, binds heparin
GM-CSF (granulocyte macrophage colony stimulating factor) Rheumatoid arthritis Induces stem cells to make granulocytes and monocycles
IL-1a Fever, insulin resistance, inflammatory pain Activates TNFa, stimulates production of PGE2, nitric oxide, IL-8 and other chemokines
IL-1b Pain, hypersensitivity Autoinflammatory syndromes, regulates cell proliferation, differentiation and death, induces COX2 activity to produce inflammatory molecules
IL-2 Itchiness, psoriasis Regulates T cell differentiation
IL-3 Drives differentiation of several cell types, including mast cells, and proliferation
IL-4 Airway inflammation, allergic asthma Regulates T cell differentiation
IL-5 Eosinophilic allergic disease Activates eosinophils, stimulates proliferation of B cells and antibody secretion, heavily involved in eosinophilic allergic disease
IL-6 Fever, acute phase inflammation, osteoporosis Inhibits TNFa and IL-1, stimulates bone resorption, reduces inflammation in muscle during exercise
IL-9 Asthma, bronchial hypersensitivity Increases cell proliferation and impedes apoptosis of hematopoietic cells
IL-10 Regulates the JAK-STAT pathway, interferes with production of interferons and TNFa.   Exercise increases levels of IL-10
IL-13 Airway disease, goblet cell metaplasia, oversecretion of mucus Induces IgE release from B cells, links allergic inflammation to non-immune cells
IL-16 Allergic asthma, rheumatoid arthritis, Crohn’s disease Attracts activated T cells to inflamed spaces,
IL-18 Linked to several autoimmune and inflammatory conditions, including Hashimoto’s thyroiditis Induces release of interferon-g, causes severe inflammatory reactions
Interferon-a Flu like symptoms, malaise, muscle soreness, fever, sore throat, nausea Inhibition of mast cell growth and activity
Interferon-b Flu like symptoms, malaise, muscle soreness, fever, sore throat, nausea Inhibition of mast cell growth and activity
Interferon-g Granuloma formation, chronic asthma Induces production of nitric oxide, IgG2a and IgG3 from B cells, increases production of histamine, airway reactivity and inflammation
Leukotriene B4 Mucus secretion, bronchoconstriction, vascular instability, pain Draws white cells to site of inflammation
Leukotriene C4 Mucus secretion, bronchoconstriction, vascular instability, pain Draws white cells to site of inflammation
MCP-1 Neuroinflammation, diseases of neuronal degeneration, glomerulonephritis Draws white blood cells to inflamed spaces,
MIF (macrophage migration inhibitory factor) Regulate acute immune response, release triggered by steroids
MIP-1a (macrophage inflammatory protein) Fibrosis Activates granulocytes, nduces release of IL-1, IL-6 and TNFa
Neurotrophin-3 Nerve growth factor
NGF (nerve growth factor) Regulates survival and growth of nerve cells, suppresses inflammation
Nitric oxide Bruising, hematoma formation, excessive bleeding Vasodilation, inhibition of platelet aggregation
PDGF (platelet derived growth factor) Platelet growth factor, growth of blood vessels, wound healing
Platelet activating factor Constriction of airway; urticaria; pain Platelet activation and aggregation, vasodilation
Prostaglandin D2 Flushing, mucus secretion, bronchoconstriction, vascular instability, mixed organic brain syndrome, nausea, abdominal pain, neuropsych symptoms, nerve pain Inflammation, pain, bronchoconstriction
Prostaglandin E2 Muscle contractions, cough Draws white blood cells to site of inflammation
RANTES (CCL5) Osteoarthritis Attracts white cells to inflamed spaces, causes proliferation of some white cells
SCF (stem cell factor) Regulates mast cell life cycle, induces histamine release
TGFb (transforming growth factor beta) Bronchial asthma, heart disease, lung fibrosis, telangiectasia, Marfan syndrome, vascular Ehlers syndrome syndrome Regulates vascular and connective tissues
TNFa (tumor necrosis factor) Fever, weight loss, fatigue Regulates death of cells and acute inflammation
VEGF (vascular endothelial growth factor) Bronchial asthma, diabetes Angiogenesis, draws white cells to inflamed spaces, vasodilation

 

 

Master table of stored mast cell mediators

Mediator Symptoms Pathophysiology
Angiogenin Tissue damage Formation of new blood vessels, degradation of basement membrane and local matrix
Arylsulfatases Breaks down molecules to produce building blocks for nerve and muscle cells
Bradykinin Angioedema, swelling of airway, swelling of GI tract, inflammation, pain, hypotension Vasodilation, induces release of nitric oxide and prostacyclin
Carboxypeptidase A Muscle damage Tissue remodeling
Cathepsin G Pain, muscle damage Converts angiotensin I to II, activates TGF-b, muscle damage, pain, fibrosis, activates platelets, vasodilation
Chondroitin sulfate Cartilage synthesis
Chymase Cardiac arrhythmia, hypertension, myocardial infarction Tissue remodeling, conversion of angiotensin I to II, cleaves lipoproteins, activates TGF-b, tissue damage, pain, fibrosis
Corticotropin-releasing hormone Dysregulation has wide reaching and severe effects Stimulates secretion of ACTH to form cortisol and steroids
Endorphins Numbness Pain relief
Endothelin Hypertension, cardiac hypertrophy, type II diabetes, Hirschsprung disease Vasoconstriction
Eotaxin (CCL11) Cognitive deficits Attracts eosinophils, decreases nerve growth
Heparin Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers Cofactor for nerve growth factor, anticoagulant, prevents platelet aggregation, angiogenesis
Histamine Headache, hypotension, pruritis, urticaria, angioedema, diarrhea, anaphylaxis Vasodilation of vessels, vasoconstriction of atherosclerotic coronary arteries, action of endothelium, formation of new blood vessels cell proliferation, pain
Hyaluronic acid Degradation contributes to skin damage Tissue repair, cartilage synthesis, activation of white blood cells
IL-8 (CXCL8) Mast cell degranulation Attracts white blood cells (mostly neutrophils) to site of infection, activates mast cells, promotes degranulation
Kininogenases Angioedema, pain, low blood pressure Synthesis of bradykinin
Leptin Obesity Regulates food intake
Matrix metalloproteinases Irregular menses (MMP-2) Tissue damage, modification of cytokines and chemokines (modifies molecules to make them useful)
MCP-1 (CCL2) Nerve pain Attracts white blood cells to site of injury or infection, neuroinflammation, infiltration of monocytes (seen in some autoimmune diseases)
MCP-3 (CCL7) Increases activity of white blood cells in inflamed spaces
MCP-4 (CCL13) Shortness of breath, tightness of airway, cough Attracts white blood cells to inflamed spaces, induces mast cell release of TNFa and IL-1, asthma symptoms
Phospholipase A2 Vascular inflammation, acute coronary syndrome Generates precursor molecule for prostaglandins and leukotrienes
RANTES (CCL5) Osteoarthritis Attracts white cells to inflamed spaces, causes proliferation of some white cells
Renin Cardiac arrhythmias, myocardial infarction, blood pressure abnormalities Angiotensin synthesis, controls volume of blood plasma,lymph and interstitial fluid, regulates blood pressure
Serotonin/5-HT Nausea, vomiting, diarrhea, headache, GI pain Vasoconstriction, pain
Somatostatin Low stomach acid symptoms, low blood sugar Regulates endocrine system, cell growth and nerve signals, inhibits release of glucagon and insulin, decreases release of gastrin, secretin and histamine
Substance P Neurologic pain, inflammation, nausea, vomiting, mood disorders, anxiety Transmits sensory nerve signals, including pain, mood disorders, stress perception, nerve growth and respiration
Tissue plasminogen activator Blood clots Activates plasminogen, clotting
Tryptase Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers; inflammation Activation of endothelium, triggers smooth muscle proliferation, activates degradation of fibrinogen, activates MMP molecules,tissue damage, activation of PAR, inflammation, pain
Urocortin Increased appetite when stressed, inflammation, low blood pressure Vasodilation, increases coronary blood flow
Vasoactive intestinal peptide Decreased absorption, low blood pressure, low stomach acid symptoms Vasodilation, mast cell activation, lowers blood pressure, relaxes muscles of trachea, stomach and gall bladder, inhibits gastric acid secretion, inhibits absorption
VEGF Diseases of blood vessels Formation of new blood vessels, vasodilation and permeability of smaller vessels

Winding in the light

I have a wound on my abdomen, a literal open wound where my stoma was. Every night I undress it, removing long thin strips of gauze before replacing them with clean packing, manipulating the tendrils with sterilized scissors. It is graphic, visceral. But I prefer to do it myself. I prefer this active stewardship of my body.

It is healing, closing up along the seams that have formed on my skin, one on each side. I am participating in the act of healing my body. Soon the line will be continuous, all the tissue underneath knitted together. Just a line that keeps a secret, like lips sewn shut. No one will ever look at this scar and know I had an ostomy until I tell them.

My GI tract is trying to figure out how to work with this new continuity. It hurts. It feels like everything holding my abdomen together on the left side is trying to give out. I am starting the very slow and arduous process of regaining strength and routine. It feels like a lot on some days. Today it feels like a lot.

But two years ago this was unfathomable. Even six months ago, I thought I knew pretty well the path my life would take it, and it was a short road, a straight line to pain and anaphylaxis and liquids and soft solids forever. I still see that road, but it is longer and it winds its way more into the light.

I don’t believe anymore that there is any fear that is so wide and so deep that you cannot meet it. I just don’t believe it.

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: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60686-7/fulltext)

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.

 

References:

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.

 

 

 

 

 

Do all mast cell patients need central lines? No. But some do.

A newer patient asked a couple of days if everyone with mast cell disease needs a PICC line, Broviac/Hickman or port for IV access. The answer is no, but I think we should talk about this a bit.

Central lines are usually given for people who need chemo or long term IV treatmet. These lines are not really designed to be left in your body forever, even ports. They generally are pulled once treatment is done, although ports can be left in for years as long as they are flushed monthly.

In my experience, mast cell patients get central lines for a few reasons:

  1. They have very poor IV access, so poor that it could delay treatment in an emergency (anaphylaxis).
  2. They get regular IV medications (this is not very common, although it’s hard to tell in this group).
  3. They regularly take IV medication that can damage veins if given frequently in peripheral veins (like Benadryl).
  4. They get them for IV hydration (it is not recommended to get a central line just for IV hydration, however some people do get them).

In the groups, it seems like there are so many patients who have these lines. Please keep in mind that those with more disabling disease are the most likely to be present in those forums. This group often also has other diagnoses for which central lines may be beneficial. On the other hand, the other group that is quite visible is the rookies. So the new patients see this very severe face on a disease which is quite manageable for many. You are seeing a subset of the population. Central lines in the mast cell community are not as common as it seems.

Regarding IV hydration, there are a few reasons why people receive this. Some of us vomit frequently and so fluids are difficult to get into us orally. Some of us have POTS or dysautonomia and have low blood volume, so the IV hydration stabilizes our blood pressure and heart rate. Some of us third space badly, and oral fluids end up in the wrong place.

This patient asked if they could just drink fluids. The answer is absolutely yes. If you can keep oral fluids down and are functioning, then I would do that. Receiving regular IV fluids can help with some symptoms, but there is no reason they need to be delivered through a central line. I used to get IV fluids at the infusion center with a new IV everytime. It is a pain but it’s not awful.

In an acute situation, IV fluids can be very helpful to mast cell patients. Long term, you need to be monitored properly as it can affect your electrolytes and for some this may raise kidney concerns. I would not get IV fluids based simply upon “feeling dehydrated”. If you “feel dehydrated” and also your blood pressure is wacky and you can’t keep down oral fluids, I think that then regular IV hydration might be useful.

I know it is frustrating to feel that you are not doing as well as you used to, but if you have mast cell disease, it is very possible you never will again, even with IV fluids. I am sorry, but that is the reality. You need to adapt to the level of ability you can manage currently.  Get some stability and things will improve.

If you and your doctor feel that IV hydration is appropriate, I would try it outpatient for a few weeks. If they then feel you need to do it at home, placing a PICC line is a good place to start. If you have a problem with the PICC line, it can be pulled without much trouble. The other lines are implanted and require surgery to remove them. The risk of bloodstream infections from central lines is real and these are very serious situations with long term effects.

Mast cell patients also run the risk of reacting to the materials used to make the line. They can also react to the maintenance of the line, such as flushing, use of heparin and alcohol swabs. This is a real problem for some people. So any time you can avoid an indwelling line long term, that is the better option.

Lastly, central lines require maintenance so you need to be sure that if your doctor wants to order one, they will also order the solutions and nursing care needed to keep you safe.

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.

 

References:

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.

 

 

 

Mast cell disease fact sheet

Mast Cell Disease

  • Mast cell disease includes all forms of disease in which your body makes too many mast cells or those mast cells do not function correctly.
  • Mast cell disease is rare, affecting less than 200,000 people in the US.
  • 90% of mast cell disease only affects the skin (edited to add: based upon estimates of mastocytosis population – counts of MCAS/MCAD not yet available).
  • The remaining 10% is systemic disease.
  • Multiple people in a family sometimes have mast cell disease, but the heritable gene has not been identified.
  • Cutaneous and systemic mastocytosis, mast cell sarcoma and mast cell leukemia are proliferative, meaning your body makes too many mast cells.
  • Mast cell activation syndrome/mast cell activation disorder are not proliferative, meaning there is a normal amount of mast cells behaving badly.
  • Monoclonal mast cell activation syndrome is borderline for proliferation, meaning the body is thinking about making too many mast cells or is just starting to.
  • The biggest risk for most mast cell patients is anaphylaxis, a severe, life-threatening allergic reaction that can be triggered by many things.
  • There is no cure for mast cell disease, but children sometimes grow out of it for unknown reasons.

Types of mast cell disease

  • Cutaneous mastocytosis (CM) is too many mast cells in the skin.
    • This causes rashes (sometimes permanent), hiving and blistering.
    • Urticaria pigmentosa (UP), telangiectasia macularis eruptive perstans (TMEP) and diffuse cutaneous mastocytosis (DCM) are the types of cutaneous mastocytosis. (Edited to include DCM.)
    • It is diagnosed by skin biopsy.
    • You can also have mast cell symptoms that aren’t related to the skin, like nausea, vomiting, weakness, headache, palpitations, etc.
    • Solitary mastocytoma is a benign mast cell tumor usually found on the skin, but sometimes elsewhere. It is sometimes included in the cutaneous mastocytosis category.
    • Children sometimes outgrow cutaneous mastocytosis.
    • When adults develop cutaneous mastocytosis, they usually also have systemic mastocytosis.
  • Systemic mastocytosis is too many mast cells in an organ that is not the skin.
    • The bone marrow is usually where too many mast cells are found, but it is sometimes found in other organs.
    • You can have systemic mastocytosis with or without cutaneous mastocytosis.
    • It is diagnosed by biopsy of an organ other than skin. Other testing like scans and organ tests may be necessary.
    • Indolent systemic mastocytosis (ISM) is stable with no organ damage. Life span is normal.
    • Smoldering systemic mastocytosis (SSM) is progressing towards a more damaging form with some signs that organ damage is beginning. Life span may be shortened if progression is not controlled.
    • Aggressive systemic mastocytosis (ASM) is a dangerous form with organ damage that requires chemotherapy to control. Life span is shorter.
    • Mast cell leukemia (MCL) is a malignant form with organ damage that requires chemotherapy. Life span is significantly reduced.
    • Mast cell sarcoma(MCS) is a malignant form with organ damage that requires chemotherapy. Life span is significantly reduced.
  • Mast cell activation syndrome (MCAS)/ Mast cell activation disorder (MCAD) is when a normal amount of mast cells behave badly. (Edited to change mast cell activation disease to mast cell activation disorder.)
    • It is clinically similar to indolent systemic mastocytosis. Life span is normal.
    • Biopsies are negative.
  • Monoclonal mast cell activation syndrome (MMAS) is when a person meets some of the criteria for systemic mastocytosis but not all. It indicates the mast cells are starting to think about abnormal proliferation.
    • It is clinically similar to indolent systemic mastocytosis. Life span is normal.
    • Biopsies are positive for one or two minor criteria for systemic mastocytosis.

Symptoms

  • Anaphylaxis
  • Skin
    • Flushing is one of the hallmark signs of mast cell disease
    • Other skin symptoms include rashes, hives, itching, angioedema, dermatographism
  • Gastrointestinal
    • Abdominal pain, diarrhea, constipation, swelling of GI tract, difficulty swallowing
  • Neurologic
    • Headache, migraine, feeling faint, numbness, pins and needles, tremors, tics, neuropathy
  • Psychiatric
    • Depression, anxiety, memory difficulties, insomnia, sleep disorders*
  • Cardiovascular
    • Weakness, dizziness, high or low blood pressure, slow or rapid heartbeat, abnormal heart rhythm, chest pain, palpitations

*Edited to add: Psychiatric symptoms are organic symptoms of mast cell disease, rather than reactive conditions from chronic illness.

This list is not exhaustive.

Triggers

  • Many things can cause mast cell reactions or anaphylaxis in mast cell patients.
  • Allergy testing (skin prick or blood testing) is inaccurate in mast cell patients as these tests assess IgE allergies and mast cell patients often have non-IgE reactions.
  • Triggers can change over time and can include:
    • Heat, cold, or rapid change in temperature
    • Friction, especially on the skin
    • Sunlight
    • Illness, such as viral or bacterial infection
    • Exercise
    • Many foods, especially high histamine foods
    • Many preservatives and dyes
    • Many medications
    • Scents and fragrances
    • Physical stress, such as surgery
    • Emotional or psychological stress

Diagnosis: Blood and Urine Testing

  • Blood test: Serum tryptase
    • This tests for the total amount of mast cells in the body, the “mast cell burden”
    • Should be tested during a non-reactive period for baseline and during a reaction
    • Time sensitive: should be tested 1-4 hours after start of reaction
    • Normal range for adults is under 11 ng/ml. (Edited to remove out of place words “is abnormal” at the end of this statement)
    • 2 ng/ml + 20% increased from baseline is indicative of mast cell activation
    • Baseline over 20 ng/ml is a minor criteria for diagnosis systemic mastocytosis
  • 24 hour urine tests:
    • N-methylhistamine
      • Breakdown product of histamine
      • Released by mast cells when reacting
      • Very temperature sensitive
      • Sample must be refrigerated and transported on ice (unless preservative is provided)
      • Measured as a ratio of another molecule, creatinine
      • Normal range for adults is 30-200 mcg/g creatinine
      • One study found that if level was 300 mcg/g creatinine, a bone marrow biopsy was likely to be positive for systemic mastocytosis
    • D2 prostaglandin and 9a,11b-F2 prostaglandin
      • Released by mast cells when reacting
      • Very temperature sensitive
      • Sample must be refrigerated and transported on ice (unless preservative is provided)
      • Normal range for both is under 1000 ng
      • 9a,11b-F2 prostaglandin is a breakdown product of D2 prostaglandin
      • 9a,11b-F2 prostaglandin is the marker for which MCAS/MCAD patients are most often positive
      • If taking aspirin or NSAIDs, these may be discontinued five days before the test or as directed by your physician
      • Other tests sometimes done in blood include heparin, histamine, prostaglandin D2 and chromogranin A.
      • Serum tryptase and 24 hour urine n-methylhistamine, D2 prostaglandin and 9a,11b-F2 prostaglandin are the tests considered to be most reliable indicators of mast cell disease.

Diagnosis: Biopsies

  • Bone marrow biopsy
    • Obtained by bone marrow biopsy and aspiration procedure
    • Stained with Giemsa and tryptase stains
    • Tested with antibodies for CD117, CD2, CD25 and CD34
    • Looking for clusters of mast cells in groups of 15 or more
    • Looking for mast cells that are shaped abnormally, like spindles
    • DNA from the biopsy should be tested for the CKIT D816V mutation, a marker for systemic mastocytosis
  • Skin biopsy
    • Obtained by punch biopsy
    • Stained with Giemsa and tryptase stains
    • Tested with antibodies for CD117, CD2, CD25 and CD34
    • Looking for clusters of mast cells in groups of 15 or more
    • Looking for mast cells that are shaped abnormally, like spindles
    • DNA from the biopsy should be tested for the CKIT D816V mutation, a marker for systemic mastocytosis
  • GI biopsies
    • Obtained by scoping procedures
    • Stained with Giemsa and tryptase stains
    • Tested with antibodies for CD117, CD2, CD25 and CD34
    • Looking for clusters of mast cells in groups of 15 or more
    • Looking for mast cells that are shaped abnormally, like spindles
    • DNA from the biopsy should be tested for the CKIT D816V mutation, a marker for systemic mastocytosis (less likely to be positive than bone marrow biopsies)
    • Mast cells should be counted in five high powered (60X or 100X) fields and the count then averaged
    • Some researchers consider an average of more than 20 mast cells in a high powered field to be high, but this is not agreed upon
    • Some researchers consider an average of more than 20 mast cells in a high powered field to be diagnostic for mastocytic enterocolitis

Treatment

  • H1 antihistamines
    • Second generation, longer acting, non-sedating for daily use
    • First generation, shorter acting, sedating, but more potent
    • Other medications with H1 antihistamine properties like tricyclic antidepressants
  • H2 antihistamines
  • Leukotriene inhibitors
  • Aspirin, if tolerated
  • Mast cell stabilizers
    • Cromolyn
    • Ketotifen
    • Quercetin
  • Epinephrine (should be on hand in case of anaphylaxis)
  • These are baseline medications for MCAS/MCAD, MMAS and ISM cell patients. If symptoms are uncontrolled, other medications may be used off label for mast cell disease.
  • Smouldering systemic mastocytosis patients may require chemotherapy.
  • Aggressive systemic mastocytosis, mast cell leukemia and mast cell sarcoma patients require chemotherapy.

Medications to Avoid

  • Medications that cause degranulation
    • Alcohol (ethanol, isopropanol)
    • Amphoteracin B
    • Atracurium
    • Benzocaine
    • Chloroprocaine
    • Colistin
    • Dextran
    • Dextromethorphan
    • Dipyridamole
    • Doxacurium
    • Iodine based radiographic dye
    • Ketorolac
    • Metocurine
    • Mivacurium
    • Polymyxin B
    • Procaine
    • Quinine
    • Succinylcholine
    • Tetracine
    • Tubocurarine
    • Vancomycin (especially when given intravenously)
    • In some patients, aspirin and NSAIDs (please ask if your doctor if these are appropriate for you)

 

  • Medications that interfere with the action of epinephrine
    • Alpha adrenergic blockers
      • Alfuzosin
      • Atipamezole
      • Carvedilol
      • Doxazosin
      • Idazoxan
      • Labetalol
      • Mirtazapine
      • Phenoxybenzamide
      • Phentolamine
      • Prazosin
      • Silodosin
      • Tamsulosin
      • Terazosin
      • Tolazoline
      • Trazodone
      • Yohimbine
    • Beta adrenergic blockers
      • Acebutolol
      • Atenolol
      • Betaxolol
      • Bisoprolol
      • Bucindolol
      • Butaxamine
      • Carteolol
      • Carvedilol
      • Celiprolol
      • Esmolol
      • Metoprolol
      • Nadolol
      • Nebivolol
      • Oxprenolol
      • Penbutolol
      • Pindolol
      • Propranolol
      • Sotalol
      • Timolol

Please note these lists are not exhaustive and you should check with your provider before starting a new medication. A pharmacist can review to determine if a medication causes mast cell degranulation or interferes with epinephrine. This list represents the medications for which I was able to find evidence of degranulation or a-/b-adrenergic activity.

Special Precautions

  • Mast cell patients require special precautions before major and minor procedures, including radiology procedures with and without contrast or dyes
  • They must premedicate using the following procedure:
    • Prednisone 50mg orally (20 mg for children under 12): 24 hours and 1-2 hours before procedure
    • Diphenhydramine 25-50 mg orally (12.5 mg for children under 12) OR hydroxyzine 25 mg orally, 1 hour before procedure
    • Ranitidiine 150 mg orally (20 mg for children under 12): 1 hour before procedure
    • Montelukast 10 mg orally (5 mg for children under 12): 1 hour before procedure
    • This protocol was developed for the Mastocytosis Society by Dr. Mariana Castells and the original can be found at www.tmsforacure.org/documents/ER_Protocol.pdf

Common coincident conditions

  • Ehlers Danlos Syndrome (EDS), especially hypermobility type (Type III)
  • Postural orthostatic tachycardia syndrome (POTS) or other types of dysautonomia
  • Mast cell disease, EDS and POTS are often found together
  • Autoimmune diseases
  • Myeloproliferative diseases, like essential thrombocythemia and polycythemia vera
  • Eosinophilic disorders

 

 

 

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 5

Deconditioning and physical inactivity are risk factors for atherosclerosis and cardiovascular disease. The cardiovascular impact of deconditioning is very well characterized and has been described in my previous posts. However, there are also a number of other system deficits induced by deconditioning.

Musculoskeletal system has the most obvious decline in response to deconditioning. A person can lose 10-20% of muscle strength in one week or bed rest. Thigh muscles can lose 3% of mass within seven days. Muscle loss is greatest in the lower back and weight bearing muscles of the legs.

After three days of continuous bed rest, contractures can form. This is the result of connective tissue and muscles being kept in a shortened position. After three weeks of bed rest, the connective tissue around joints changes to stabilize the joint in a shortened position.

Osteoporosis can occur in deconditioned patients. This is called “disuse osteoporosis” as it occurs because the bones are not bearing weight. When the bones are not bearing weight, the pressure of the body and gravity is not applied to the bones. This causes the bone cells to be resorbed at an abnormal rate, with liberated calcium entering the blood stream. After twelve weeks of bed rest, bone density can be almost 50% less. This effect is most pronounced in the long bones. Cartilage degeneration and osteoarthritis can also occur, along with a variety of other bone specific complications.

Frequent episodes of bed rest can also increase the risk of blood clots forming. This in turn can cause pulmonary embolism, in which a blood clot blocks one of the arteries in the lungs.

Bed rest causes a number of pulmonary concerns as well. Over time, reduced muscle strength and endurance causes less movement of the diaphragm, intercostal and abdominal muscles. Mucous becomes trapped in the airways and impaired cilia are unable to move it out. This can cause a cough and eventually develop into pneumonia.

Deconditioned patients often experienced decreased appetite, lower gastric secretion, constipation, impaired absorption and atrophy of the mucosa and glands in the GI tract. Excretion of water and salt is increased. 15-30% patients on bedrest develop kidney stones and urinary tract infection is not uncommon. Deconditioned patients have less lean body mass and develop more fat. Nitrogen metabolism becomes disordered and minerals and electrolytes are excreted more quickly than appropriate.

Frequent bed rest can compress peripheral nerves, especially the perineal and ulnar nerves. Cognition is also affected. These patients find focusing difficult and judgment and problem solving impaired. Pain threshold becomes lowered, making pain worse. Anxiety, fear and depression are more commonly found in deconditioned patients than in the general population. Sensory processing is affected, increasing the auditory threshold so that sounds must be louder to be heard correctly.

Bed rest can also affect the patient’s circadian rhythm, temperature and sweating response and provoke glucose intolerance. A number of hormones, including thyroid, adrenal and pituitary hormones, undergo altered metabolism and regulation. After two weeks of bed rest, two weeks of resumed activity is needed before glucose behavior returns to base line.

 

References:

Bleeker, Michiel W.P., et al. Vascular adaptation to deconditioning and the effect of an exercise countermeasure: results of the Berlin Bed Rest study. Journal of Applied Physiology (2005); 99(4); 1293-1300.

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

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.

 

References:

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.