The shadow edge

I was in the process of applying to medical school when it started to become obvious that I was sick. I chose not to complete the application process out of fear that I would be accepted and too sick to attend. I ultimately got much worse and would definitely have been too sick for medical school. As it turned out, I was sick for several years. And in the last couple of years, I have been too sick to do much of anything.

I am 31 years old. I finished school almost eight years ago. I have been sick for that entire duration. Somehow in my mind, being sick is recent, a brief interruption to my normal state. Eight years is not brief. I have now been sick longer than it took me to complete my undergraduate and graduate degrees.

In the middle of those years is the time when most people transition from one stage of life to the next. It is the time when you take fun vacations, go to parties, focus on your career, meet your significant other, marry. They achieve their earlier goals and move onto the next ones. They grow up, calm down and settle down.

I was sick for those years and never really made that transition. There is still a riot, loud and unyielding, in my heart.

I have dreams for 31, but I also had dreams for 25 and 28. When do you have to let them go? At what point do you not have enough time?

In some ways, it is easier when all of your dreams are washed away at once. It is harder to choose which dreams to lose. It is hard to accept that those years weren’t lost, but that they prevented me from achieving these things that are so important. Those years may prevent me from ever achieving some of them.

I feel a lot better these days than I have in a couple of years.  But now that I feel more functional, I find myself constantly taking inventory of life, of the things I never did and the things I might still be able to do, if I start right now.  It is overwhelming sometimes.  It feels like the shadow edge of hope.

I knew I would one day run out of time to do everything, that eventually pushing things into the future would mean they fell over the edge and disappeared forever. It just happened sooner than I thought.

Mast cell interactions with B and T cells

Mast cells communicate with many other cells of various types in the body. The type of communication we have discussed here most often is via mediator release – mast cells release mediators and they trigger an action in another cell by binding to a receptor, or the other cells release mediators that act on mast cell receptors. Another method of interaction is for cells to physically contact with each other. Mast cells use these techniques to impact the behavior of other cells.

B cells are lymphocytes, a kind of white blood cell. They form part of the adaptive immune system, the arm of immunity that is learned over the course of your life. They make antibodies when exposed to allergens or antigens from infectious agents. They help amplify the immune response during infection, can release cytokines and some become memory B cells, which allow for rapid response to a previously encountered organism.

Mast cells produce and release IL-4, IL-5, IL-6 and IL-13, all of which regulate the development of B cells and which role they develop toward. Mast cells can induce IgE production by B cells via binding of OX40 on the B cell to the OX40 receptor on the mast cell. In the absence of an activating signal, mast cells are able to cause unactivated B cells to proliferate and become IgM producing cells.

Resting and activated mast cells inhibit B cell death and promote proliferation of undifferentiated B cells. When the B cells are activated, this effect is exaggerated. These changes occur when mast cells and B cells are in contact and mast cells have released IL-6. Activated mast cells can drive B cells toward becoming CD138+ plasma cells or producing IgA.

T cells are also lymphocytes. There are several types of T cells and all perform very specialized functions. Mast cells and T cells are often found in close physical proximity in inflamed spaces. Conditions in which this commonly occurs include sarcoidosis, irritable bowel disease, rheumatoid arthritis and prolonged allergic processes.

Contact between mast cells and T cells initiates gene expression in mast cells. When the T cells are activated, it also induces mast degranulation, production/release of TNFa, release of MMP-9, inhibition of MMP-1, and release of IL-4 and IL-6. This occurs due to binding between the surface molecules LFA-1 and ICAM-1. Another receptor on mast cell surfaces, LTβR, can be bound by T cells. This initiates release of IL-4, IL-6, TNFa, CXCL2 and CCL5 by mast cells. In the presence of TNFa, binding to OX40 on activated CD4+ T cells by mast cells causes T cell proliferation and cytokine production.

Mast cells can express proteins on their surfaces called major histocompatibility complex I and II. These proteins literally show pieces of a phagocytosed, or “eaten”, pathogen. Showing these pieces to other cells allows them to fight infection in a specialized way. When mast cells express MHC II, they can steer T cells toward developing into specific types, including Treg cells. When mast cells express MHC I, they increase CD8+ T cell populations and ability to kill infectious agents. CD8+ T cells can cause MHC I expression by mast cells.

Mast cells and Treg cells are found in close proximity in secondary lymphoid and mucosal tissues. Activated Treg cells reduce the amount of IgE receptors on mast cells when they come into contact. They also cause release of TGF-b and IL-10. Treg cells interfere with degranulation via the OX40 receptor on mast cells.

References:

Gri, Giorgia, et al. Mast cell: an emerging partner in immune interaction. Front. Immunol., 25 May 2012.

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. Clin. Exp. Allergy 2004; 34, 1725–1731.

 

June 2014: Post summaries and take home points

Cutaneous mastocytosis

  • CM is mastocytosis limited to the skin.
  • About 90% of mastocytosis patients have CM.
  • 2/3 of CM cases are found in children.
  • Many children “grow out” of their CM.
  • Adult onset CM tends to develop into SM.
  • All types of CM are positive for Darier’s sign.
  • Darier’s sign is a wheal and flare response when touching mast cell lesions due to histamine release.
  • CM is diagnosed by biopsy.
  • Urticaria pigmentosa (UP) is also called maculopapullar cutaneous mastocytosis (MPCM).
  • UP is the most common form of CM.
  • UP is marked by tan or red/brown lesions that usually start on the trunk.
  • UP lesions are very itchy.
  • UP accounts for 65-90% of CM cases in children and 47-75% overall.
  • UP can cause systemic symptoms.
  • Mastocytomas are benign mast cell tumors.
  • Solitary mastocytomas are often grouped with CM because they usually occur on the skin.
  • Mastocytomas can also occur internally.
  • 10-35% of CM cases are single mastocytomas.
  • Multiple mastocytomas are unusual but can occur.
  • Diffuse cutaneous mastocytosis (DCM) is rare, accounting for 1-5% of CM in children.
  • DCM is the most severe presentation of CM.
  • DCM usually presents in early infancy and is almost always diagnosed before three years of age.
  • DCM lesions can cover much of the body and may blister and bleed.
  • DCM can cause thickening of the skin.
  • Telangiectasia macularis eruptiva perstans (TMEP) is relatively rare and found almost exclusively in adults.
  • TMEP lesions are usually smaller than UP and do not itch.  (Note added on 7/26/15 – a few patients have reached out to let me know that they have TMEP and it does sometimes itch, especially when triggered.  I’m going to look back at the previous source and see if the author of that article was incorrect or if I misunderstood.  I will add my findings into both this post on the original June 2014 post.  Thanks!)
  • The only way to distinguish UP from TMEP is biopsy.
  • Blistering can occur with any form of CM.
  • Patients with frequent blistering are more likely to have systemic symptoms and anaphylaxis.

Histamine: intended functions and mast cell symptoms

  • Histamine is produced mostly by mast cells and basophils.
  • It can be stored inside cells or immediately released and used.
  • A breakdown product of histamine is n-methylhistamine. This is what we test for in 24 hour urine samples.
  • Histamine performs its functions by interacting with four known histamine receptors, H1, H2, H3 and H4.
  • H1 receptors are present in the nervous system including the brain.
  • H1 activity helps regulate the sleep-wake cycle, body temperature, appetite, mood, pain levels and other hormones.
  • H1 activity also causes airway constriction, difficulty breathing, hives and itching.
  • Histamine increases wakefulness.
  • H2 receptors are mostly found in the GI tract and vascular tissues, but some are present in the skin.
  • H2 activity can cause vessels to dilate, decreasing blood pressure.
  • H2 activity induces acid release in the stomach.
  • H3 receptors are in the nervous system.
  • H3 activity regulates release of neurotransmitters, including histamine, acetylcholine, norepinephrine and serotonin.
  • H4 receptors are found in many parts of the body and are involved in inflammation.

Effect of mast cell mediators on sleep

  • About half of histamine in the brain released by mast cells.
  • Histamine increases wakefulness.
  • Histamine activity increased during food deprivation or starvation, so regular meals can help sleep.
  • Chronic fight or flight type stress can increase the number of mast cells in the brain.
  • Prostaglandin D2 induces deep sleep.
  • Mild to moderate inflammation increases production and release of PGD2, making you tired.
  • Severe inflammation induces release of PGE2, which stimulates mast cells to release histamine.
  • Sleep in patients with high PGE2 is fragmented and not deep.

Gene expression and the D816V mutation

  • DNA is a molecule that contains the genetic code for all living organisms and some viruses.
  • DNA in humans is two strands wrapped around each other in a double helix.
  • RNA is similar to DNA but not the same.
  • RNA helps to express certain genes using the code from DNA.
  • Genes tell the cell how to make proteins or RNA that has a specific function.
  • D816V means that at codon 816 (a location in the CKIT gene), a mutation changed the code from making one amino acid (aspartic acid) to another one (valine).
  • Some people with mast cell disease don’t have the D816V mutation, but may have other CKIT mutations.

 

 

June 2015: Post summaries and take home points

Mast cells in wound healing
• When a wound occurs, the complement system is activated to form a clot.
• Complement molecules activate mast cells and induce degranulation.
• Mast cells work to prevent excessive clotting.
• Mast cells break down the extracellular matrix to make room for new cells to close the wound.
• Mast cells drive generation of new blood vessels.
• Histamine and tryptase mediate formation of new muscles.
Angioedema: Part 1
• Hereditary angioedema (HAE) is a heritable blood disorder that causes episodes of protracted swelling that can be life threatening.
• Angioedema is when fluid leaves the bloodstream and gets trapped between the deep dermis and subcutaneous tissue.
• Swells can last up to five days.
• About 30% of HAE patients get a pink ring rash.
• HAE patients do not have hives or itching.
• Swelling can affect any part of the body.
• Swelling of the tongue and throat can cause suffocation.
• Abdominal swells are often misinterpreted as “acute abdomen” requiring surgery.
• 85% of patients have type I.
• 15% have type II.
• Type III cases are rare.
• All three are treated similarly.
• Bradykinin causes blood vessels to dilate, decreasing blood pressure and causing fluid to become trapped in tissues.
• C1 inhibitor (C1INH) regulates the C1 protein, which activates the complement system (for fighting infections), controls formation of blood clots and generation of bradykinin.
Angioedema: Part 2
• In HAE type I, C1 inhibitor (C1INH), C4 and C2 levels are low; C1q is normal.
• In HAE type II, C1INH is normal or a little increased, C4 and C2 are low, C1q is normal; C1INH functions poorly.
• In HAE type III, C1INH is normal and functional; C4 may be normal.
• HAE attacks can cause airway constriction leading to suffocation.
• More than half of HAE patients will experience this type of swelling at least once.
• Swells usually last 2-3 days and then resolve.
• Antihistamines and steroids do not resolve this type of swelling.
• HAE has many triggers in common with mast cell disease, including foods, estrogen level, psychological stress and physical triggers.
• Cinryze, Berinert and Ruconest are C1INH solutions for IV use.
• Kalbitor is a kallikrein inhibitor for SQ injection.
• Firazyr is a bradykinin receptor blocker for injection.
• Medications like danazol and tranexamic acid are seeing less use with several new meds available.
Angioedema: Part 3
• Acquired angioedema (AAE) patients have deficiency of C1 esterase inhibitor (C1INH) that is not due to genetic defect.
• AAE is ten times less common than HAE.
• AAE often presents with low CH50, C2, C4 and sometimes C1q, poorly functioning or low C1 esterase inhibitor (C1INH).
• AAE can occur secondary to many autoimmune and hematologic diseases.
• Type I AAE has poor function of C1INH.
• Type II AAE has autoantibodies to C1INH.
• Idiopathic angioedema is three episodes of angioedema in 6-12 months without a clear reason.
• Type III HAE patients sometimes have mutations in the Factor XII gene, but not all.
• Type III patients have four attacks a year on average.
• Estrogen levels are more likely to induce angioedema in Type III patients than in other types of angioedema.
• Bruising and clotting issues are sometimes seen in type III HAE patients.
Angioedema: Part 4
• Deficiencies of complement molecules C1q, C1r, C1s, C2, C4 are associated with lupus like autoimmune conditions.
• Without these molecules, dead cells and debris cannot be removed and cause local inflammation.
• In HAE types I and II, complement molecules C2 and C4 are low.
• Deficiency in C2 and C4 might predispose to autoimmune disease.
• One study found 13.2% HAE patients had autoantibodies to thyroid.
• 47.5-48% of HAE patients had at least one autoantibody when tested with a panel for several autoantibodies.
• On average, 10% of the healthy population has at least one autoantibody.
• 12% of HAE patients had autoimmune disease when tested with a panel for several autoimmune conditions.
• HAE patients often have a decreased sense of smell.
• HAE patients have increased B cell activation and autoreactive B cells, which contributes to autoimmunity.
Activating the complement system: Classical, alternative and lectin pathways
• The complement system is many proteins that can circulate in the bloodstream.
• Other proteins can cut off pieces of these proteins to activate the proteins.
• Once the proteins are activated, they help kill infecting organisms.
• The classical pathway is activated by C1 protein when microbes are present.
• The alternative pathway is activated by the C3 protein changing into C3b.
• The lectin pathway is activated by two proteins called MBL and ficolin binding to the surfaces of microbes.
• These pathways release C3a and C5a, which activate mast cells.
• C1 inhibitor (C1INH) inactivates C1r and C1s to stop the complement pathway.
Deconditioning, orthostatic intolerance, exercise and chronic illness – Part 6
• Exercise can treat deconditioning due to orthostatic intolerance.
• Exercise can also exacerbate symptoms in deconditioned patients.
• It is worse when coupled with hot weather or eating before exercise.
• A sustained hand grip will raise blood pressure for a short time.
• Performing the hand grip when changing position or after exercising or eating can help mitigate OI symptoms.
• Leg crossing while tensing muscles can also help regulate blood pressure before standing.
• Multiple studies have demonstrated that regular exercise can help manage POTS.
• Recumbent exercise is helpful when starting to work out as it is less likely to trigger OI symptoms.
• Some patients are able to recover significant capability and are able to engage in athletic activities.
• Exercise for chronic fatigue and fibromyalgia patients has also had success in improving deconditioning symptoms and quality of life.
Deconditioning, orthostatic intolerance, exercise and chronic illness – Part 7
• Volume expansion (use of IV hydration or volume expander like dextran) can improve symptoms in deconditioned patients.
• Volume expansion does not improve exercise capacity.
• IV saline with exercise gives the best results for symptom relief.
• Volume expansion can mitigate the effect of heat stress on the body.
• Volume expansion alone stabilized blood supply to the head.
• 86% of POTS patients in a study reported IV saline as the best treatment for brain fog.
• Mast cell degranulation can cause hypotension and vasodilation.
• Mast cell mediator release can cause fluid loss from blood resulting in edema.
• Volume loading in the form of IV fluids may decrease mast cell symptoms due to deconditioning, orthostatic intolerance and capillary leakage.

Mast cells in kidney disease

Kidneys are essentially large filters. Blood is passed through endothelial cells in blood vessels, then filtered through a membrane made up of structural molecules. The filtrate then moves into kidney tubules where it becomes urine and is pushed out towards the bladder. During this process, the kidneys carefully remove substances from urine and put other substances into it in order to regulate available water, electrolyte concentration and blood pressure.

Chronic kidney disease can be caused by a variety of insults, including diabetes, high blood pressure, genetic conditions, chemical exposure, damage from shock, autoimmune disease and infections. Regardless of the underlying reason, once the kidney is injured, it can become sclerosed and fibrosed if not healed correctly. This can ultimately cause kidney failure. The kidney is able to function well even when a significant portion is damaged. For this reason, kidney disease is often not identified until 60-70% of functional kidney cells have been damaged beyond repair.

Mast cells have very complex and nuanced roles in renal disease. In healthy kidneys, mast cells are rare. In the presence of kidney disease, mast cells form a significant infiltrate, with counts increasing by as much as 60 times compared to healthy controls. IgA nephropathy, lupus nephritis, diabetic nephropathy and renal tubulointerstitial fibrosis are all conditions in which mast cell count has been correlated with degree of kidney fibrosis. Mast cell growth factors such as stem cell factor (SCF) are elevated in affected kidney tissue. However, mast cell count has not been shown to be related to severity of disease in any models thus far.

Mast cells are not the only allergic actor involved in kidney disease. Atopy (having allergic conditions like atopic dermatitis or allergic asthma) has been linked to idiopathic nephrotic syndromes in which patients experience kidney damage for unknown reasons. These patients often have multiple severe allergies and have serum IgE levels higher than found in other kidney diseases. Furthermore, IgE levels stay high in patients that relapse. Allergy immunotherapy and trigger avoidance has been trialed in these patients with mixed results. Many researchers believe that in these patients, the nephritis and allergies are both manifestations of one underlying condition.

IgE levels are also increased in nephritis caused by lupus (SLE). Basophils, different cells involved in allergies, make antibodies to IgE, causing an inflammatory response and worsening this type of nephritis.

Kidney damage can be caused by heavy metals and chemicals, including some types of chemotherapy. Tryptase is significantly elevated in patients with this kind of damage. In these patients, neutrophils and CD4+ T cells quickly infiltrate affected kidney tissue. In animal models where they are mast cell deficient, this infiltration by neutrophils and T cells is less efficient. This means that mast cells are involved in drawing these cells to the kidney. Treatment of the tissue with cromolyn also decreases the level of infiltration.

Mast cells are known to participate in fibrosis both in the kidney and elsewhere. Mast cells release fibrosis driving molecules like type VIII collagen in diabetic nephropathy; fibroblast growth factor in IgA nephropathy; and release tryptase, chymase and carboxypeptidase A, which participate in remodeling and fibrosis, in a number of conditions. Tryptase can also cause proliferation of fibroblasts.

Fibrosis develops largely due to the activity of TGFb and angiotensin II, which can be regulated by mast cells. Chymase can generate angiotensin II, which increases blood pressure and can further aggravate kidney conditions. In biopsies for which chymase staining is positive, fibrosis is significant. Renin, a molecule that regulates angiotensin II, is also released by mast cells.

In spite of these data, there is also significant evidence that in some instances, mast cells are protective against kidney disease. In some research models where mast cells are deficient or absent, kidney damage progresses more quickly. Levels of IL-4 and TGFb1, which can drive kidney damage, are higher in mast cell deficient models. Heparin, a mast cell mediator, is known to interfere with production of TGFb1.

In some cases, mast cells even protect against kidney fibrosis. Mast cells have been found to degrade fibronectin, which other cells need to filtrate the kidney. Mast cells can also prevent deposition of fibrin and type I collagen, which contributes to fibrosis.

References:

Madjene, LC., et al. Mast cells in renal inflammation and fibrosis: Lessons learnt from animal studies. Molecular Immunology 63 (2015) 86-93.

Blank, U., et al. Mast cells and inflammatory kidney disease. Immunol Rev 2007, 217: 79-95.

Summers, SA., et al. Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction. Kidney Int 2012.

May 2015: Post summaries and take home points

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

  • Deconditioning is when the body becomes acclimated to less physical stress and becomes less able to function properly under normal conditions.
  • Bed rest can cause deconditioning.
  • The cardiovascular system changes within 24 hours of bed rest.
  • In less than a week, 10% of blood volume is lost.
  • When deconditioned, your body does not make appropriate changes when changing position.
  • This is called orthostatic intolerance (OI).
  • Chronic illness can cause deconditioning.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2

  • Orthostatic intolerance(OI) is symptoms that interfere with or prevent standing up.
  • OI affects heart rate, blood pressure and distribution of blood to the brain.
  • In OI, the body incorrectly initiates a fight or flight response.
  • Orthostatic hypotension is a reduction of systolic blood pressure of more than 20 mm Hg or diastolic blood pressure of more than 10 mm Hg within three minutes of standing.
  • POTS patients have daily OI symptoms with excessive tachycardia when standing (increase of 30 bpm when standing or over 120 bpm in adults).
  • Postural syncope (fainting) can be caused by orthostatic intolerance or vasovagal syncope (VVS).
  • Fainting is caused by lack of blood flow to the brain.
  • Mast cell disease is known to cause orthostatic intolerance.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3

  • POTS (postural orthostatic tachycardia syndrome) is one type of orthostatic intolerance (OI).
  • POTS is characterized by an increase of heart rate of 30 bpm or more when standing in the absence of orthostatic hypotension.
  • Neuropathic POTS is caused by the veins in the legs not constricting enough to maintain blood pressure when standing.
  • Hyperadrenergic POTS is caused by the nervous system telling the heart to beat faster and harder.
  • HyperPOTS patients have fluctuating or elevated blood pressure, tachycardia, hypertension and excessive sweating.
  • One study found that 38% of mast cell patients had hyperPOTS.
  • One study found that 28.9% of POTS patients had less blood volume than normal.
  • POTS patients have persistent tachycardia, push less blood out of the heart per beat than normal, have a smaller than normal part of the heart, and do not use oxygen effectively during exercise.
  • POTS is often associated with conditions that provoke exercise intolerance, like fibromyalgia, chronic fatigue syndrome and deconditioning.

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

  • Syncope (fainting) is loss of consciousness due to temporary loss of blood supply to the brain.
  • About 40% of people will faint in their lifetime.
  • Vasovagal syncope(VVS) is a form of orthostatic intolerance (OI).
  • VVS is often preceded by lightheadedness, sweating, weakness, nausea and visual disturbances.
  • VVS patients can go long periods without OI symptoms.
  • Ingestion of 16 oz of water in five minutes effectively treats OI episodes of all types.
  • OI symptoms can be triggered by large meals, sudden change in position, extended time laying down, heat and alcohol.
  • Physical maneuvers and compression garments can decrease OI symptoms in some patients.
  • Increasing salt and water intake is recommended for adults with orthostatic hypotension or POTS.

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

  • Deconditioning and physical inactivity increase risk for cardiovascular disease.
  • A person can lose 10-20% of muscle strength in one week of bed rest.
  • Muscle loss is greatest in lower back and legs.
  • After three days of bed rest, connective tissue and muscles begin to contract.
  • Osteoporosis is more likely in deconditioned patients.
  • After twelve weeks of bed rest, almost 50% of bone density can be lost.
  • Frequent bed rest increases risk of blood clots.
  • Bed rest can reduce strength of muscles supporting the respiratory system, leading to cough and pneumonia.
  • 15-30% of bedrest patients develop kidney stones.
  • Frequent bed rest can cause neurologic, cognitive and psychiatric disturbances.
  • Thyroid, adrenal and pituitary hormones become dysregulated with bed rest.

Exercise and mast cell activity

  • Exercise induces mast cell degranulation and release of newly made mediators.
  • Histamine, tryptase and leukotrienes increase following exercise in patients who have exercise induced bronchoconstriction.
  • Treating with montelukast and loratadine suppressed release of histamine and leukotrienes.
  • Leptin is elevated in obese patients.
  • Leptin makes airways more reactive and more inflamed.
  • Leptin increases the allergic response including leukotriene production.
  • Asthmatics who are obese are less likely to respond to inhaled corticosteroids but respond to anti-leukotriene medications.
  • Leukotriene E4 was elevated in both obese and lean asthmatics after exercise.
  • 9a,11b-PGF2 (metabolite of PGD2) was elevated in obese and lean asthmatics after exercise.

Histamine depletion in exercise

  • Regular exercise can be protective against asthma.
  • Histamine is released in lungs due to exercise.
  • Histamine becomes depleted during exercise.
  • Plasma epinephrine does not rise in asthmatics following exercise.
  • Inhalation of cromolyn before exercise can prevent or mitigate induced asthma in many patients.
  • Treating with H1 and H2 antihistamines decreased endurance during exercise.
  • Histamine is important in inducing exercise tolerance.

Chronic urticaria and angioedema: Part 3

  • There are several pathways that can cause urticaria and angioedema:
  • IgE activation of mast cells
  • C3a and C5a activation of mast cells
  • Production of bradykinin
  • IgG activation of mast cells
  • NSAIDs
  • Non-immunologic methods such as radiocontrast dyes, pressure on the skin, heat, etc.

Chronic urticaria and angioedema: Part 4

  • There are several conditions that present similarly to chronic urticaria and angioedema.
  • Development of urticaria during pregnancy is not unusual.
  • Cutaneous mast cell patients often have urticaria like lesions.
  • MCAS can also cause angioedema and urticaria.
  • Angioedema in the absence of urticaria is rare.
  • Hereditary angioedema (HAE) is caused by deficiency or dysfunction of C1 esterase inhibitor in most patients.
  • HAE patients do not have coincident urticaria.
  • Acquired angioedema is caused by antibodies to the C1 esterase inhibitor, which can be from cancer.
  • Angioedema can affect any part of the body.

Chronic urticaria and angioedema: Part 5

  • Treatment scheme:
  • Second generation H1 antihistamine
  • Increase dose of second generation H1 antihistamine
  • Add another second generation H1 antihistamine
  • Add an H2 antihistamine
  • Add a leukotriene receptor antagonist.
  • Add a first generation H1 at bedtime.
  • Add a strong antihistamine like hydroxyzine.
  • Consider Xolair or immunosuppressants.

Premedication and surgical concerns in mast cell patients

  • Exact incidence of immediate anaphylaxis from surgery or anesthesia is unknown in mast cell patients
  • Mast cell patients should premedicate for surgery.
  • Anxiety, temperature changes, irritation of skin, physical trauma and pain can all cause mast cell activation.

 

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

This universe inside

Last summer I went to Maine with my sister, cousins and some friends for my cousin’s bachelorette party. I had a PICC line and couldn’t swim, was throwing up most of my food and the loop of bowel behind my stoma twisted on itself. I slept a lot and spent all day in the hotel room with air conditioning in order to muster enough energy to go out at night. I still had a good time largely due to good company, but it was a good time I fought pretty damn hard for.

This past weekend, I went back to Maine with the same group of girls with a couple of substitutions. We stayed in a hotel with a pool about 200 yards from the ocean. It was sweltering in a way that makes even healthy people tired. I crossed my fingers and hoped for the best.

On Saturday night, we all went out and had a nice dinner at a restaurant in town. After, I went for a long walk before bed. It was still hot and sticky out, but the wind blowing off the ocean felt like a big hug. It was one of those nights when you feel connected to the world. The waves crashed on the beach, this soft, wet percussion. The stars were bright.

It felt like I could look all the way across the universe. It felt like I could look all the way across my universe, the one I contain inside my body. I walked along the water and thought about my limits, the limits of that expanse.

The next morning, I deaccessed my port, put on my bathing suit and sunglasses, and went to the beach. I waded into the ocean. The water was cold, but not frigid. I floated in the shallows, rising and falling with waves. It was very serene.

I took some IM benadryl at lunch since I was deaccessed. I went swimming in the ocean again. I swam in the pool. I reaccessed my port. I ate a fancy dinner at a nice restaurant. I fell asleep at a reasonable hour, slept all night and woke up in the morning. The trip was completely uneventful concerning my health. My body worked fine the entire time.

It doesn’t feel like this is my body. It is like I borrowed one, a better model. It continues to demonstrate its new durability. Eating sweet potato fries with ketchup. Taking the train to and from work. Being in the office 3-4 days a week. Walking in oppressive heat. Swimming in the ocean. Thirty minutes of cardio. It is tolerant. Sturdy, even.

I am torn between being cautious in this capable new vessel and pushing all the limits. I am afraid of not knowing how far I can go. I am scared that all of this will go away.

But it’s here now. It feels like the universe inside me is expanding, the boundaries pushed further away with every beat of my heart.

July 2014: Post summaries and take home points

Mast cell disease and the spleen

  • The spleen removes old or damaged red blood cells.
  • It holds a supply of blood cells that can be released in case of hemorrhage.
  • It recycles iron from old red blood cells.
  • It filters out bacteria.
  • When the bone marrow is not producing enough blood cells, the spleen can make red and white blood cells.
  • Swelling of the spleen is called splenomegaly.
  • If you can feel the spleen, it is at least twice its normal size.
  • Swelling of the spleen may have no symptoms, but it can cause referred pain, especially in the shoulder.
  • If the bone marrow is not producing enough blood cells, the spleen can become swollen because of the stress of making so many cells.
  • Swelling of the spleen is pretty common in blood disorders.
  • Swelling of the spleen is a B finding in SM. If you have two B findings, you have smoldering systemic mastocytosis.
  • Hypersplenism is when the spleen is working too hard.
  • Hypersplenism with splenomegaly is a C finding, which means you have aggressive systemic mastocytosis.
  • Hypersplenism is indicated by swelling of the spleen, reduction in red blood cells, platelets or granulocytes, increased cell production by the bone marrow, and probable resolution if the spleen is removed.
  • Hypersplenism can cause additional complications like ascites (free fluid in the abdomen) and port hypertension (increased pressure in the vein between the GI tract and spleen).
  • Portal hypertension and ascites are also C findings.
  • Removal of the spleen can improve prognosis.
  • Patients with no spleen are more susceptible to certain types of infections.

Cost of US Healthcare

  • In 2010, the US spent an average of $8233 per patient.
  • The US spends 17.6% of GDP on healthcare, compared to other developed nations which average 9.5%.
  • The US has fewer practicing physicians and fewer hospital beds.
  • In the US, we spend 2.5x more on ambulatory care, such as walk-in clinics and emergency rooms.
  • We do not have enough PCPs in the US.
  • Administrative cost per patient is much higher in the US, partly due to not having electronic records.
  • The US performs more tests than other countries.
  • Five year survival rates for many cancers are best in the US.
  • Access to newer medications and treatments is more readily available in the US.

Third spacing

  • The human body keeps fluids in two spaces called compartments.
  • The first compartment is inside cells.
  • The second compartment is outside of the cells, like in the tissues around the cells.
  • The second compartment holds 40% of fluids.
  • Third spacing is when your fluids collect outside of one of these two compartments.
  • Fluid in a third space is unusable by the body.
  • Ascites, pulmonary edema and angioedema are all forms of third spaces.
  • Third spacing can compress structures around the fluid.
  • Third spacing can sometimes affect organ function.
  • Third spacing can cause the fluid level in the circulatory system to drop.
  • People with frequent third spacing often have symptoms of dehydration.
  • Third spacing can occur due to anaphylaxis or mast cell activation.
  • IV fluids are helpful for some patients who have third spacing.

Sex and chronic illness series: Vaginal pain

  • Vulvodynia is vulvar pain without an obvious cause.
  • Vulvodynia can cause burning, stinging or sharp pain in the vulva, labia and vaginal opening.
  • Vaginal penetration can be painful with vulvodynia.
  • Any pressure on the genital area, including sitting, can be painful with vulvodynia.
  • Vulvar vestibulitis is a subset of vulvodynia found in 10-15% of women who receive regular gynecological care.
  • Women with a chronic pain disorder like interstitial cystitis or fibromyalgia are three times more likely to have vulvodynia.
  • If they have more than one pain disorder, their risk increases over five fold.
  • 73% of vulvodynia have no other known chronic pain disorder.
  • Mast cells have been linked to sexual pain disorders.
  • Allergic reactions or mast cell degranulation may cause vulvodynia.
  • Vulvodynia patients have high numbers of degranulated mast cells in biopsies.
  • Wearing cotton underwear and avoiding scented products can help vulvodynia.
  • Oxalate rich diets can irritate vulvodynia but do not cause it.
  • Creams with cromolyn are effective for vulvodynia pain.
  • Physical therapy and biofeedback can help pelvic floor dysfunction.
  • If penetration is painful, dilation can be helpful.
  • A vestibulectomy is a last resort and is about 80% effective.
  • About 116 million people in the US live with chronic pain.

Antibiotics (part one)

  • Bacteria are categorized by the way they are shaped and grouped, and how they derive energy.
  • Bacteria are also categorized by their reaction to a test called a Gram stain.
  • Antibiotics inhibit the growth of or kill microbes, including bacteria.
  • Medications that kill fungi are called antimycotics or antifungals.
  • Antivirals kill viruses, but viruses are not technically alive.
  • Some antibiotics are only effective against specific types of bacteria. These are called “narrow spectrum” antibiotics.
  • Some antibiotics are effective against many types of bacteria. These are called “wide spectrum” antibiotics.

Antibiotic resistance (part two)

  • It took less than five years for antibiotic resistance to develop to penicillin, the first widely used antibiotic.
  • Using antibiotics unnecessarily contributes to antibiotic resistance.
  • Antibiotics do not treat viral infections.
  • If you get repeat, frequent infections of the same nature, you need to see an infectious disease specialist.

Mast cell leukemia

  • Less than 1% of mastocytosis cases are MCL.
  • It can occur in a patient who previously had mastocytosis or with no history of mast cell disease.
  • MCL patients have bone marrow infiltration of at least 20% mast cells and infiltration of internal organs.
  • CKIT D816V mutation is not always present.
  • Median survival is six months.
  • Swelling of spleen and liver are common in MCL patients.
  • Only 1/3 of MCL patients have skin involvement.
  • In 25% of MCL cases, CD25 is not expressed; in 33%, neither CD25 nor CD2 is expressed.
  • Average age of diagnosis with MCL is 52 years old.
  • 27% of patients had a history of mastocytosis.
  • Only four cases recorded of children with mastocytosis evolving into MCL.
  • In one case, a child with a mastocytoma developed MCL.
  • Treatment is largely experimental.
  • Seven patients have received stem cell transplants. All have died in less than three years.

Diagnosis of mast cell diseases

  • Cutaneous mastocytosis, including UP, TMEP and DCM (diffuse cutaneous mastocytosis), is diagnosed by biopsy.
  • Mastocytoma can also be diagnosed by biopsy, but urtication on touching is usually diagnostic.
  • SM has one major and four minor criteria. You must meet one major and one minor, or three minor criteria for diagnosis.
  • The most common method for diagnosing SM is bone marrow biopsy, but biopsy from any non-skin organ may meet criteria.
  • SM patients are biopsy negative 1/6 of the time.
  • The blood test for the CKIT D816V mutation is not always reliable. Bone marrow is more reliable.
  • Serum tryptase criterion for SM is baseline tryptase, not reaction tryptase.
  • There are three criteria for SM called B findings that show disease progression. If you have two or more B findings, you have smoldering systemic mastocytosis.
  • There are five criteria for SM called C findings that show aggressive disease. If you have one or more C findings, you have aggressive systemic mastocytosis.
  • Mast cell leukemia is usually diagnosed through bone marrow biopsy.
  • Mast cell sarcoma is a very aggressive tumor that converts to mast cell leukemia. It is diagnosed by biopsy.
  • Mast cell sarcoma is different from mastocytoma.
  • Mast cell activation syndrome (MCAS) is diagnosed by evidence of mediator release, presence of mediator release symptoms, response to mast cell medications and absence of another cause for mast cell activation.

 

 

August 2014: Post summaries and take home points

Myelodysplastic syndrome (MDS)

  • Umbrella term for disorders in which body does not produce enough myeloid cells and the cells produced do not function correctly.
  • Myeloid cells are a type of white cells including eosinophils, basophils, neutrophils and mast cells.
  • MDS patients have low blood counts.
  • Sometimes asymptomatic.
  • Spleen is often swollen.
  • Bone marrow biopsy is diagnostic.
  • There are a number of causes of MDS.
  • Stem cell transplant may be considered in severe cases.
  • Transplant has 50% survival after 3 years.
  • Majority of MDS patients progress to acute myeloid leukemia (AML).
  • 23% of SM-AHNMD have SM and MDS.

Cutaneous mastocytosis and systemic symptoms

  • Urticaria pigmentosa (UP) and telangiectasia macularis eruptiva perstans (TMEP) are forms of cutaneous mastocytosis (CM).
  • CM is caused by dense infiltrates of mast cells in the skin.
  • Skin is the organ most likely to be infiltrated by mast cells.
  • Patients with UP or TMEP who do not have SM can still have symptoms affecting organs other than the skin.
  • CM patients can have shortness of breath, low blood pressure, nausea, vomiting, diarrhea and other mast cell symptoms.
  • Mast cell mediators release in the skin can move through the tissue and trigger other mast cells.
  • The more skin covered by rash, the more likely systemic reactions are.
  • Having systemic symptoms does not mean you have SM.
  • If you develop CM as an adult, you are likely to develop SM.
  • Chronic elevation of tryptase, expression of CD25 by skin mast cells or presence of D816V CKIT mutation can indicate SM will develop.
  • Systemic symptoms in CM are treated the same way as in SM or MCAS.
  • MCAS does not refer to a state of reactivity or severe symptoms.

The question I get asked the most

  • SM is not cancer.
  • It is not cancer because the cells do not proliferative enough to endanger life.
  • Most SM patients have indolent disease, for which life expectancy is normal.
  • ASM has more features in common with cancer.
  • MCL is cancer.

Anticholinergic effects of mast cell medications

  • Anticholinergics block the molecule acetylcholine from sending signals in the central and peripheral nervous sytems.
  • Blocking acetylcholine can cause many side effects, including:
  • Decreased GI motility
  • Dry mouth and throat
  • Dilation of pupils
  • Rapid heart rate
  • Visual disturbances
  • Urinary retention
  • Cognitive issues
  • Myoclonic jerks
  • A lot of antihistamines are anticholinergics.
  • Cyproheptadine, promethazine, desloratadine, loratadine, diphenhydramine, clemastine, doxepin, doxylamine, ipratropium, hydroxyzine and meclizine are anticholinergics.
  • Alprazolam, diazepam, ranitidine, prednisone and hydrocortisone may be anticholinergics.
  • Cetirizine and fexofenadine are not anticholinergics.

Pregnancy in mastocytosis

  • Many allergic conditions are exacerbated by menses.
  • Sex hormones influence mast cell activation and degranulation.
  • Mastocytosis patients often discontinue antihistamine and antimediator medications during pregnancy.
  • During pregnancy, 45% of mastocytosis patients had itching, 40% had flushing, 24% had GI symtpoms, 9% had anaphylaxis.
  • 22% had worsened symptoms throughout pregnancy.
  • 18% developed new symptoms.
  • 33% had improved symptoms during pregnancy.
  • 15% had complete resolution of symptoms.
  • All resolutions occurred during the first trimester and most lasted throughout the pregnancy.
  • Anaphylaxis during pregnancy was resolved without epinephrine.
  • 45% had no change in symptoms during pregnancy.
  • Anesthesia and medications for labor were safe in mastocytosis patients.
  • Premedication at initiation of labor is recommended.
  • Rate of prematurity and birth complications were similar to general population.

Histamine effects on neurotransmitters (serotonin, dopamine and norepinephrine)

  • Medications that block the H1 receptor increase dopamine release.
  • Histamine stimulates prolactin release via the H2 receptor, which inhibits dopamine production.
  • Histamine can increase metabolism of norepinephrine, serotonin and dopamine.
  • About 40% of serotonin released by mast cells.
  • Serotonin causes many GI symptoms.
  • Mast cells release dopamine.
  • Frequent mast cell activation decreases dopamine production.
  • Dopamine can be converted to norepinephrine.
  • Dopamine is responsible for cognitive alertness.
  • Norepinephrine is responsible for concentration and vigilance.
  • Increased histamine increases norepinephrine production and secretion.