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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

Gastroparesis: Part 1

Gastroparesis (GP) is a condition in which stomach contents are not emptied into the small intestine within an appropriate time period without an obvious anatomical explanation.  Gastroparesis patients are highly symptomatic, with approximately 90% reporting nausea, 84% vomiting, and abdominal pain, bloating, feeling unable to eat more after a small portion and feeling very “full” after even a small meal.  Some patients can manage their symptoms with dietary changes and medication, while others continue to be significantly symptomatic.

In some people, GP manifests episodically, with no symptoms for periods of time between flares.  In others, symptoms are chronic and perpetual.  Malnutrition, dehydration and weight loss can be severe in some cases.  Despite the primary functional feature of gastroparesis being the delayed emptying of the stomach, the degree to which gastric emptying is slowed correlates poorly with symptoms and severity of symptoms.

Gastroparesis affects at least 37.8 women/100000 persons and 9.6 men/100000 persons.  Once thought to be uncommon, it is now thought that gastroparesis may affect up to 2% of the population.  Hospital admissions for gastroparesis have increased dramatically in the last two decades, with a 158% increase between 1995 and 2004, with 138% of that increase occurring between 2000 and 2004.  There are several possible reasons for this phenomenon, including changes to criteria, better recognition and the withdrawal of cisapride from the market, a medication that alleviated some gastroparesis symptoms.

Gastroparesis is marked by generic gastrointestinal symptoms which can make it hard to identify unless the clinician is familiar with this condition.  Initially, it is often mistaken for functional dyspepsia.  For patients who have distinct episodes rather than continuous symptoms, patients are sometimes misdiagnosed with cyclic vomiting syndrome.

Gastroparesis can occur as a result of a number of diseases or circumstances.  Diabetes and surgery are the most commonly reported causes.  Idiopathic gastroparesis, in which no specific cause can be found, is often the most common in patient groups studied, with up to 1/3 of patients having this type.  Autonomic neuropathy, connective tissue diseases, autoimmune disease, thyroid disease can also cause gastroparesis, among many other conditions.

 

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

How to activate mast cells: Receptors and Ligands Master Table (part 3)

Receptor Ligand (molecules that bind to the receptor) Result
Nicotinic acetylcholine receptor Acetylcholine Increases severity of anaphylaxis
NOD1, NOD2 Bacterial products Cytokines; dependent upon ligand
Paired Ig-like receptor B (PIR-B) Inhibitory
Peripheral benzodiazepine receptor Benzodiazepines Inhibits mediator release
Platelet endothelial cell adhesion molecule (PECAM-1) Inhibitory
Progesterone receptor Progesterone Inhibits mediator release
Prostaglandin E receptors, EP2, Prostaglandin E Downregulates IgE mediated response, inhibits prostaglandin and leukotriene production

 
Prostaglandin E receptors, EP3, EP4 Prostaglandin E Increases IgE mediated degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Increases IgE dependent cytokine production

 
Protease activated receptors 1-4 (PAR1-4) Serine proteases (trypsin, tryptase, chymase) Histamine release, mast cell activation
Purinoreceptor P2Y11 ATP Production of prostaglandins and leukotrienes
Purinoreceptor P2Y2 ATP, UTP Production of prostaglandins and leukotrienes
Purinoreceptors P2Y1, P2Y12, P2Y13 ADP Production of prostaglandins and leukotrienes
Sialic acid binding Inhibitory
Sphingosine-1-phosphate S1P1 Sphingosine-1-phosphate Chemotaxis

 
Sphingosine-1-phosphate S1P2 Sphingosine-1-phosphate Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

De novo:
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 
ST2 IL-33 Cytokines
TGFb receptor 1 TGFb Decreases IgE dependent degranulation, IgE dependent TNF production
TLR1-9 Bacterial and viral products Cytokines ; dependent upon ligand
Urokinase receptor Urokinase Movement of mast cells
Vitamin D receptor Vitamin D Mast cell development
β2-adrenoreceptor Adrenaline Inhibits FcεRI degranulation and cytokine production and secretion

How to activate mast cells: Receptors and Ligands Master Table (part 2)

Receptor Ligand (molecules that bind to the receptor) Result
Gp49B1 Gp49B1-αvβ3 Inhibits IgE activation
GPCR mimetic MRGX2 Mastoparan, cortistatin, PAMP-12, somatostatin, neuropeptide FF, oxytocin, substance P Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin
GPR34 Lysophosphatidylserine, b defensins, LL-37?? Enhances degranulation:  Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo:

PGD2, PGE2, LTC4, IL-2, IL03, IL-5, IL-1b, TNF, IL-31, GM-CSF, IL-5, TNFg
GPR92 Lysophosphatidic acid Cytokine production and release
Ig-like lectins Inhibitory
IL-10 receptor IL-10 Decreases IgE dependent release of IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
IL-3 receptor IL-3 Increases IgE dependent release of histamine and leukotriene C4
IL-4 receptor IL-4 Increases IgE dependent release of histamine, leukotriene C4 and IL-5 release
IL-5 receptor IL-5 Increases IgE dependent secretion :
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 
Leptin receptor Leptin Immunomodulation
Cysteinyl Leukotriene receptor 1, 2 Leukotrienes Cytokine production and proliferation
LPA1, LPA3 Lysophosphatidic acid Encourage development
Mast cell function associated antigen (MAFA) Inhibitory
MHC I Antigenic peptides For activating other immune cells
MHC II Antigenic peptides For activating other immune cells
MRGX2 Mastoparan, somatostatin, substance P, platelet factor 4, mellitin

 

 Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo: IL-3, IL-8, TNFa, GM-CSF
Myeloid associated Ig-like receptor 1 Unknown Inhibition of mast cell activation and mediator release
Neurokinin receptors: NK1R, NK2R, NK3R, VPAC2 Substance P, CGRP, hemokinin A, VIP, nerve growth factor, neuropeptide Y Substance P: Degranulation:

Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

Produce and release cytokines

 

VIP, Neuropeptide Y: induce release of histamine

 

CGRP:

Degranulation:

Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin
Neurotensin receptor Neurotensin Degranulation
Neurotrophin receptor TrkA NGF Degranulation: histamine, serotonin, NGF
Neurotrophin receptor TrkB BDNF, NT-4 No degranulation
Neurotrophin receptor TrkC Neurotrophin 3 No degranulation

All the favors in pharmacy land

For most of my adult life, I have had the feeling that I didn’t have any money. I worked full time in college, and two full time jobs in grad school. I worked full time for a biotech company after I graduated, while also working side jobs. I certainly worked a lot for not having money.

At some point, I sat down and went through all my finances in detail. I looked at years of bank statements, credit card statements and student loan agreements. I tallied how much I spent on gas, on car repairs, on food, on fun. But none of those were the issue. I had one expense that was more than all of those put together: medical bills.

I literally just sighed as I typed that sentence. And you know what? I bet all the sick kids reading this sighed along with me. I don’t even get mad about it anymore. I am just resigned. Sigh.

I accepted a temporary position at my current company about two years ago. After six months as a contractor, I accepted a full time position. My contractor insurance was garbage and I needed comprehensive coverage badly. I eagerly flipped through the insurance information packets, basking in the golden glow of great medical coverage. It was overwhelming and wonderful. It was also a little sad that I was barely 30 years old and so excited about copayments and yearly out-of-pocket maximum costs that only had three zeros at the end.

I signed up for PPO insurance, which for our non-American readers means I can pick which doctors I see without being referred by my primary care physician (PCP, usually called general practitioner in other countries). There are caveats to PPO plans, but it is overall less restrictive and therefore desirable for me, as I often need specialist appointments on short notice.

In the US, it is not unusual for your medical insurance (doctor visits, hospital stays, medical supplies) to be managed by a different and completely separate company from your prescription coverage. So when I picked my PPO insurance, I also had to pick a large prescription carrier that forced upon the unwitting masses the bane of my existence: mail-order prescriptions.

I worked in pharmacy for about ten years. In that time, prescription insurance companies directly caused most of the issues that made my job frustrating and difficult. The prescription carrier I got along with my (amazing, approves everything) PPO is well known for rejecting claims for stupid reasons. But I needed a PPO and this was the corresponding prescription insurance. I didn’t have a choice.

So I got my new prescription insurance card and used it to fill my monthly medications at my local pharmacy. That went okay for a couple of months. Then I got a notification that my insurance would only pay for three fills of a maintenance medication (one that is taken all the time as part of your baseline care). Any fills after that would have to be filled with a mail order pharmacy.

Because I need a million strange things, I called my health insurance case manager. She sympathized but had nothing to do with pharmacy benefits. I told her that I had called the prescription company and asked for a case manager. They wouldn’t give me one. She couldn’t do anything.

The mail order pharmacy got new prescriptions for my meds from my doctors. They filled them and shipped them out to me. I opened the first huge box of meds and immediately knew something was wrong. I take ondansetron (zofran) 8mg three times a day every day. I have done this for years. I have tried to decrease and it always goes very badly. I have a prior authorization done every year to approve for 270 tablets/90 days for four total fills to coverage three a day dosing for the entire year. The pharmacy received a prescription that said that.

Except the person filling the prescription looked at it and thought, nobody takes three of these a day every day. Surely this is a mistake! And bless their hearts, they did me the huge favor of correcting that prescription from 270 with 3 refills to 27 with 30 refills. That’s much better.

So I had nine days of zofran. I called them and told them what happened. I was on the phone for two hours. They told me it was all set and they were sending the rest. Three days later, a package arrived. It had one bottle of 27 ondansetron.

I’m not going to bore you with the sordid details because I bet you all know where this is going. You know, right? Yup. Nine phone calls and every single one of them went exactly the same way except by the ninth, I was crying in frustration. I was out of my medication and every time I called, they told me it was all set and they fixed the error. And then nine more tablets would show up and we would start all over again.

This is a repeating cycle. The mail-order pharmacy is forever filling my 270 tablet (insurance approval obtained) prescription for 27 tablets.

So, mail order pharmacies are difficult. I don’t think that is surprising anyone here. But at the same time as this was going on in what I assume was a distant state where everyone is brainwashed to reassure me that they are fixing my problem right before they throw my precious bottles of ondansetron into a bottomless pit, I started having some problems closer to home.

I still got some prescriptions filled at my local pharmacy (this is entirely at the discretion of the pharmacy insurance.) There were only three I got filled locally regularly – prednisone, fluticasone nasal spray, and Epipens. Last October, I was counting out my prednisone 1mg tablets to put into my pill organizer when I realized there were a bunch of 5mg tablets mixed in with the 1mg tablets. I had been sick for three weeks and wondering why I felt decent one day and miserable the next. That would be because I was dispensed two strengths of a medication for which 1mg differences matter a lot. So that sucked. I called the pharmacist and she apologized and filled my script with 1mg tablets instead of both and I got on with my life. I understand that mistakes get made sometimes. It’s fine.

Then in December, this same pharmacy lost a prescription from my PCP. In May, they lost a prescription for prednisone for premedication before surgery. I had called the previous week to make sure it was there and sent my mother to pick it up on the Monday before my Wednesday surgery. It was gone. So that was quite a circus getting that straightened out the day before major surgery. The district pharmacy supervisor called me and we had a long conversation about my weird diseases and surgery and she apologized and I needed to go have surgery so I just let it go.

Two weeks ago, I called to get my Epipens filled. I had a new prescription that was on file from March. Guess what, guys? GUESS WHAT. That prescription was gone, too.

At this point, I just hung up the phone because I was about to start screaming. I called the district pharmacy supervisor on Monday and she went by the pharmacy to pull the original prescription book from the day it was sent over in March. It was there. It was filled, returned to stock and never put on hold. This was three prescriptions, all from different offices, in under a year, with a dispensing error right off the top.

While I was dealing with the Epipen situation, I ordered refills for all of my mail order meds and GUESS HOW MANY ONDANSETRON CAME IN MY ORDER. JUST. GUESS.

I called the poor nurse at my PCP’s office who does all my prior authorizations and I literally sobbed over how sick I was of fighting for things like meds to not vomit up everything I eat. This woman is a saint and she tag teams my insurance company with me to get things taken care of. To demonstrate my gratitude, I hereby bestow upon her the internet moniker of Nurse Amazing.

In the last two weeks, Nurse Amazing and I made over a dozen phone calls between us and had the same conversation over a dozen times. After one particularly hopeless day, she asked if my IV meds were covered under my medical benefit. They are. “If we have to, maybe we can just call in enough IV Zofran to get you through.” HOW DO I LIVE IN A WORLD WHERE IT IS EASIER TO GET IV MEDS THAN NON-CONTROL SUBSTANCE TABLETS WITH NO POTENTIAL FOR ABUSE? HOW IS THE WORLD LIKE THIS?

The Universe cut me a break this time. I finally got the rest of my ondansetron delivered Saturday.

While Nurse Amazing was on the phone with my insurance, she noticed my Enbrel prescription was about to expire so she gave them a new one over the phone. “She hasn’t taken this since last year,” the agent told the nurse so apparently they are also throwing away any record of my monthly order for this (refrigerated, requires signature and scheduled delivery) medication. My Enbrel arrived expediently with no paperwork of any kind. Just a labelled box of prefilled syringes, an ice pack and nothing else.

I just went to pick up my Epipens. The pharmacist did not apologize and did not look the least bit like she gave a shit that I have spent over 65 hours in the last three weeks trying to fill my medications at SIX pharmacies as required by insurance (for those keeping score: retail pharmacy, mail order pharmacy, specialty mail order pharmacy for Enbrel, a second retail pharmacy that stocks one of my harder to source meds, compounding pharmacy for ketotifen, IV pharmacy for IV push meds/infusions). And you know what? It’s one thing to make consecutive mistakes, and it’s another thing to make consecutive mistakes and act like I am an asshole for expecting my medications to be filled and tracked correctly.

“This copay is high but I can only charge you half because of what happened,” she said. Where ‘what happened’ meant they lost the prescription for my lifesaving epinephrine autoinjectors.

“I would appreciate it if you would waive the copay in light of all the time spent getting this straightened out,” I said in my most exhausted voice both because I am so exhausted and also because it was either exhaustion or screaming vulgarities.

“Fine,” she said. You know that voice people use when they think they’re doing you a favor, like they’re giving you something that you shouldn’t expect? It was that voice. “Fine.” In that voice. I signed, took my Epipens and left.

On my way home, I remembered that I got shorted needles by my IV pharmacy (which has never made a mistake with my meds or supplies.) I stopped by the other pharmacy in walking distance because I just did not want to go back to the one where the pharmacist was doing me favors.

In Massachusetts, you can buy syringes without a prescription if you’re over 18. I walked up to the counter with my license out and prepared myself for the inevitable condescension that usually accompanies buying syringes without a prescription.

The technician came right over. “I need twenty syringes, inch long needle, any gauge you want,” I said.

“Okay,” she said, smiling. “Any specific volume?”

“It doesn’t really matter. My infusion pharmacy just didn’t send me enough for this week.”

“Well, that’s not okay,” she said and you know what? SHE ACTUALLY MEANT IT. “I’ll bring over a few and you can pick.”

She brought over a few types and I picked the one I wanted and she rang me out.

As a demonstration of my appreciation for her smile and sympathy, she shall hereafter be known as Technician Amazing throughout all the lands. I have a dream that one day she will be successively promoted to the position of Supreme Pharmacy Ruler and she will decree that it shall be illegal to provide any less than 270 tablets of ondansetron when the prescription says 270 tablets of ondansetron.

Probably won’t happen like that. But it’s okay to dream.

Privilege

My body is changing. I am tired but do not sleep for twenty hours at a time. Bones and angles emerge as my swelling wanes. I exercise. I eat real food. I sleep at night.

At the same time, I am carefully engineering to encourage these continued changes. I still take a ton of medication. I still need IV fluids every day. I still need IV meds. I still need to manage my pain. I still need to be careful. This nethervoid I currently inhabit might never be mistaken for healthy, but it is healthy for me. It is stable at least, predictable. It is good for me.

Last week was composed of the oppressive, sticky summer days that Boston is known for. Heat, humidity and sunlight form my own personal triad of doom. I got halfway through my short walk between stations and started reacting badly. I went into a Starbucks and promptly threw up while hives appeared on my neck. All of my exposed skin was bright red. I took some Benadryl and drank some cold water and waited for things to calm down. They did. I continued on my way to work.

It is hard for me to gauge how bad I look on any given day, as I was for many years in a persistent reactive state. My only indication is that initial surprise when people look at me, that flash of concern as their eyes widen, a brief moment before they recover. I knew as soon as I got to work that I must look terrible.

We have a cold room at work that is essentially an enormous refrigerator. “Girl, you need to go stand in there,” one of my coworkers said with a supportive nod. So I did. It helped. When I emerged, multiple people told me they were worried I would anaphylax and to please take a cab home. I am so fortunate to work with this group of caring, wonderful people that understand my disease and want me to be safe.

I did end up taking a cab home. I didn’t want to, but I did. It’s hard for me to articulate why I didn’t want to, when I knew it was safer and easier, in a way that doesn’t make me sound crazy. Getting in that cab made me sad in this nebulous but palpable way.

Taking the train to work is a privilege. Going to work, cleaning your house, paying your bills, food shopping, making dinner, eating solids, crunching lettuce as you watch television, being part of the world. These are privileges. These are the things you miss when you are hospitalized or so tired that your whole body feels heavy or riding that knife’s edge of anaphylaxis because your body is fighting you on something you need to do.

All of the days you spend fighting – this is what it is for. You fight for these privileges. You fight to be in the world. These are the things you will miss. All you can ever hope for is to wake each day to a world full of mundane privileges.

Some days I want to take the train even if there is a chance I will get sick. Because there is a chance that I won’t. Once that was impossible. Maybe it will be again. Maybe tomorrow it will be impossible, but not today.

I am still sick. I am still in pain. I still have a poorly functioning GI tract. I still carry two Epipens and a backpack full of meds everywhere I go. I am still nauseous. After all of the effort put forth in the last three months, I did not get cured. I got to walk to work sometimes. I got to eat salad. I got to feel the sunlight on my skin. That’s what I got. And it’s enough, and even more than it’s enough, it’s amazing. All of this is amazing. I am alive this summer and I am alive in the heat and I am alive when I’m too hot and I’m alive in the sun.

You cannot always decide what you do, but you can always decide who you are. I cannot always walk in the summer sun, but I am always a person who wants to.

I choose to live in the world and to enjoy it and be alive. I choose this even when it might hurt me. I choose this even when it might kill me. It is where I want to be.

It is a privilege to participate in this world. It is a privilege to be alive.

How to activate mast cells: Receptors and ligands Master Table (part 1)

There are many receptors on mast cells.  The molecules that bind to these receptors are called ligands.  Different receptors can cause activation in different ways.

I am posting this table a little at a time as I anticipate getting a lot of questions about it.  I put this together for my own reference and I didn’t keep track of all sources.  I am hoping to go through the literature again and track this at some point.

These tables are not exhaustive, and I’ll add to them over time as I have the chance.

Receptor Ligand (molecules that bind to the receptor) Result
0X40 0X40 ligand Suppression of mast cell activation
A2A, A2B, A3 Adenosine At low concentration, degranulation:

histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

De novo: IL-1b, IL-3, IL-4, IL-8, IL-13

 

At high concentration, inhibits FcεRI degranulation
C3α receptor C3α De novo:
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Increases IgE and IgG dependent degranulation
C5α receptor C5α Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 
Cannabinoid CB2 receptor 2-arachidonoyl-glycerol, anandamide Suppression of mast cell activity
CCR1 CCL3 (MIP1α), CCL5 (RANTES) Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
CCR3 CCL11 No degranulation
Increases IgE dependent secretion: IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
CCR4 CCL2 (MCP-1) No degranulation, reléase of cytokines
CCR5 CCL3 (MIP1α), CCL5 (RANTES), CCL4 (MIP1β) No degranulation, reléase of cytokines
CD200 receptor CD200 (OX2) Inhibitory
Cd300α receptor Eosinophilic granule proteins Inhibitory
CD47 (integrin associated protein, IAP) Integrins Histamine secretion
CD48 E. coli, M. tuberculosis Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

De novo : TNFa, IL-6
CD72 CD100 Inhibits CKIT activation
CKIT receptor tyrosine kinase (CD117) Stem cell factor De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
Corticotropin/ corticotropin releasing hormone receptor CRH, urocortin Secretion of VEGF
CX3CL1 Fractalkine No degranulation
CX3CR1 Chemokines No degranulation, reléase of cytokines
Estrogen receptor Estrogens Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
ETA Endothelin-1 Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo: TNFa, IL-6, VEGF, TGF-b1
ETB Endothelin-1 Unknown
FcαR (CD89) IgA Unknown
FcγRIIA, FcγRI, FcγRIIIA IgG/antigen Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
FcγRIIIB IgG/antigen Cannot induce activation
FcεRI IgE with or without antigen Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

Antihistamine Table: Generics and US brand names

 

First generation  
Benztropine Cogentin
Brompheniramine Dimetapp, Bromfed
Carbinoxamine Palgic
Chlorpheniramine Chlor-Trimetron
Clemastine Tavist
Cyproheptadine Periactin
Dexbrompheniramine Drixoral
Diphenhydramine Benadryl
Doxylamine Unisom, Nyquil
Hydroxyzine Atarax, Vistaril
Meclizine Antivert, Bonine, Dramamine
Orphenadrine Norflex
Prometheazine Phenergan
Second and third generation
Acrivastine Semprex-D
Cetirizine Zyrtec
Clemastine Tavist
Desloratadine Clarinex
Fexofenadine Allegra
Ketotifen N/A
Levocetirizine Xyzal
Loratadine Claritin
Tricyclic antidepressants
Amitriptyline Elavil
Clomipramine Anafranil
Desipramine Norpramin
Doxepin Silenor
Imipramine Tofranil
Nortriptyline Pamelor
Protriptyline Vivactil
Atypical antipsychotics
Aripiprazole Abilify
Asenapine Saphris
Clozapine Clozaril
Iloperidone Fanapt
Olanzapine Zyprexa
Paliperidone Invega
Quetiapine Seroquel
Risperdone Risperdal
Ziprasidone Geodon
Typical antipsychotics
Chlorpromazine Thorazine
Fluphenazine Prolixin
Perphenazine Trilafon
Prochlorperazine Compazine
Thioridazine Mellaril
Thiothixene Navane
Tetracyclic antidepressants
Amoxapine N/A
Loxapine Loxitane
Maprotiline Ludiomil
Mirtazapine Remeron

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.