gi symptoms

Reintroduction of food to a child with SM

by Lisa Klimas
February 14, 2017April 28, 2017

I recently put together some recommendations on reintroducing foods to a child with SM who has been exclusively on IV nutrition (TPN) for an extended period of time. I thought you might find some use in it so I have posted it here.

Before people ask, there are no significant publications on children with MCAS because there are not currently unifying diagnostic criteria.

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Author’s note: I am not a medical doctor. Protocols for reintroducing foods must be developed by the managing care team and tailored to each patient.

There are no large population studies for pediatric systemic mastocytosis. True systemic mastocytosis (in which WHO diagnostic criteria are satisfied) is rare in children. Accordingly, SM in children is generally reported as case reports rather than studies given the population size[i].

Given the lack of in depth literature specifically regarding food challenge in children with SM, I would draw from data in similar situations to identify a safe and appropriate protocol for reintroducing for [name redacted].

There are five scenarios that may contribute insight for food reintroduction in this patient: oral food challenges for FPIES patients; desensitization procedures for delayed hypersensitivity reactions; reintroduction of food after long term parenteral therapy; premedication of patients with mast cell activation disease, including systemic mastocytosis; and mast cell involvement in gastroparesis, ileus and GI dysmotility.

Based upon these scenarios, we can infer the following:

Reintroduction of food to this patient should follow a long, repetitive schedule with gradually increasing quantities.
Premedication with antihistamines and glucocorticoids to avoid mast cell reaction should be considered.
Mast cell activation can directly induce GI dysmotility. Drug management of mast cell activation can suppress impact upon function.
Enteral feeds should be gradually increased while parenteral feeds are gradually decreased.

	Scenario	Application to food reintroduction in a mast cell patient
1	Oral food challenge in setting of FPIES	FPIES and food reactions secondary to mast cell disease are both non-IgE mediated and can culminate in shock requiring emergency intervention.
2	Desensitization for delayed drug hypersensitivity reactions	Mast cell degranulation and anaphylactic reactions are not type I hypersensitivity reactions. They may also present on a delayed schedule.
3	Reintroduction of food after long term parenteral nutrition	Reintroducing food to patients after long term parenteral nutrition may impact GI function. Gradual reintroduction is recommended.
4	Premedication of patients with mast cell activation disease	Patients with mast cell activation disease, including systemic mastocytosis, are advised to premedicate prior to all procedures to decrease risk of reaction and anaphylaxis.
5	Mast cell involvement in gastroparesis, ileus, and GI dysmotility	Mast cells contribute significantly to GI motility disorders including gastroparesis and ileus.

Oral food challenge in patients with food protein induced enterocolitis syndrome (Caubet 2014[ii], Leonard 2011[iii])

Food protein induced enterocolitis syndrome (FPIES) is a severe non –IgE mediated GI food hypersensitivity syndrome. Patients with FPIES are children. The condition is managed by removing the offending food from the diet for extended periods, usually years.
Food challenge in FPIES can result in severe, repetitive vomiting; diarrhea; lethargy; pallor; hypothermia; abdominal distension; and low blood pressure. Not all of these features are universally present for all patients.

The following procedure is recommended for oral food challenge in FPIES children:
All FPIES oral food challenges must be physician supervised with appropriate supportive care available.
Over the first hour, 0.06-0.6 g/kg body weight of food protein should be administered in three equal doses. It should not exceed 3g of total protein or 10g of total food or 100ml of liquid for initial feeding.
If patient has no reaction, give a full serving of food as determined by their age.
Observe patient for several hours afterward.
In the event of severe reaction, administer 1mg/kg methylprednisolone intravenously, up to 60-80 mg total; 20 ml/kg boluses of NS; and epinephrine.
Food challenge is considered positive for reaction if patient experiences typical symptoms as a direct result of the challenge.

Desensitization for delayed hypersensitivity medication reactions (Scherer 2014[iv], Leoung 2001[v])

There are no controlled studies available on desensitization for delayed reactions to drugs.
Described procedures have timespans ranging from hours to weeks.
Patients who initially failed rapid protocols have succeeded using slower procedures.
It may take 2-3 days before hypersensitivity symptoms develop in a delayed reaction.
Long protocols with repetitive, gradually escalating dosing are recommended.
Antihistamine prophylaxis is often recommended. Drug and dosing vary.
The following procedure describes an example of a gradually escalating dosing:

Dose escalation for desensitization, adapted from antibiotic desensitization procedure (Leoung 2001)[v]
Dosing level	Drug portion	Frequency of daily dosing
1	12.5%	QD
2	25%	BID
3	37.5%	TID
4	50%	BID
5	75%	TID
6	100%	QD

Reintroduction of food after long term parenteral nutrition (Hartl 2009[vi], Oley Foundation)

Long term TPN may increase intestinal permeability.
Long term TPN may result in diminished enzymatic activity in GI mucosa.
The Oley Foundation suggests decreasing parenteral nutrition by 25% while increasing enteral feeds by 25% as the patient tolerates.

Premedication of patients with mast cell activation disease (Castells 2016[vii])

Mast cell patients are recommended to premedicate for all procedures using H1 and H2 antihistamines, glucocorticoids, and leukotriene receptor antagonists.

Mast cell involvement in gastroparesis, ileus, and GI dysmotility (Nguyen 2015[viii], de Winter 2012[ix])

Mast cells can be activated by a number of pathways which do not involve IgE, including neuropeptides, complement factors, cytokines and hormones.
Mast cells in the GI tract are closely associated with afferent nerve endings.
Mast cell behavior in the GI tract is largely controlled by the central nervous system.
Mast cells are directly involved in GI dysmotility disorders including gastroparesis and ileus.
Mast cell activation and population may be upregulated in the setting of GI inflammation.

[i] Lange M, et al. (2012) Mastocytosis in children and adults: clinical disease heterogeneity. Arch med Sci, 8(3): 533-541.

[ii] Caubet JC, et al. (2014) Clinical features and resolution of food protein induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol, 134(2): 382-389.

[iii] Leonard S, et al. (2011) Food protein induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol, 107:95-101.

[iv] Scherer K, et al. (2013) Desensitization in delayed drug hypersensitivity reactions – an EAACI position paper of the Drug Allergy Interest Group. European Journal of Allergy and Clinical Immunology, 68(7): 844-852.

[v] Leoung GS, et al. (2011) Trimethoprim-sulfamethoxazole (TMP-SMZ) Dose Escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. Journal of Infectious Diseases, 184:992-997.

[vi] Hartl WH, et al. (2009) Complications and monitoring – Guidelines on Parenteral Nutrition, Chapter 11. Gen Med Sci, 7:Doc17.

[vii] http://www.tmsforacure.org/documents/ER_Protocol.pdf

[viii] Nguyen LA, et al. (2015) Clinical presentation and pathophysiology of gastroparesis. Gastroenterol Clin N Am, 44: 21-30.

[ix] de Winter BY, et al. (2012) Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Act, 1822: 66-73.

Chromogranin A

by Lisa Klimas
February 12, 2017April 28, 2017

Chromogranin A is a protein secreted in several environments. While it is primarily released in the adrenal medulla with catecholamines (norepinephrine, epinephrine, dopamine, and others), CgA is often found stored in the granules of endocrine cells in the GI tract. CgA is the precursor molecule for several active molecules. Vasostatin-1 and -2 are involved in regulation of various effects of the cardiovascular system, including blood pressure and stroke volume, by opposing the action of catecholamines. Catestatin decreases release of catecholamines. Pancreastatin decreases insulin secretion. A number of other molecules are also derived from CgA.

Chromogranin A and its derivatives are biomarkers for several conditions. 60-80% of neuroendocrine tumor patients demonstrated elevated chromogranin A. A connection with Alzheimer’s disease has recently been reported. Rheumatoid arthritis and lupus patients may have elevated CgA as a result of increased tumor necrosis factor. Various forms of cancer, kidney disease, and elevated cortisol can also impact chromogranin A level.

Elevated CgA has also been linked to a number of inflammatory GI conditions. 30-50% of IBD patients with active disease have elevated serum CgA. In ulcerative colitis, fecal chromogranins were elevated but not correlated with disease activity. Conflicting results have been seen in patients with Crohn’s disease. Some studies have reported an increased amount of CgA containing cells in patients with IBS.

There are a number of methods for quantifying chromogranin A. Proton pump inhibitors and H2 antihistamines can yield false positive results. A study compared several commercial kits for measuring chromogranin A and found that the radioimmunoassay (RIA) kit was most likely to be accurate with a sensitivity of 93% and specificity of 85%. This means that 93% of the time, this kit properly identified patients with high CgA as having high CgA, while 85% of the time, it properly identified patients with normal CgA as having normal CgA. Currently, there are multiple test methods for quantifying serum and plasma CgA with no central standardization.

Chromogranin A is a constituent of granules in rat mast cells. Tumor necrosis factor is a mediator released by mast cells and may also influence the levels of chromogranin A in mast cell patients. One study found that 31.5% of patients with mast cell activation disease (in a cohort mostly composed of MCAS patients) demonstrated elevation of serum CgA. This same study concluded that plasma heparin and 24 urine testing for prostaglandin D2 and 9a,11b-prostaglandin F2 were the most sensitive markers for mast cell activation with other mediators being less effective.

References:

Gut P, et al. (2016) Chromogranin A – unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci, 12(1): 1-9.

Wernersson S, Pejler G. (2014). Mast cell secretory granules: armed for battle. Nature Reviews Immunology, 14: 478-494.

D’Amico MA, et al. (2014) Biological function and clinical relevance of chromogranin A and derived peptides. Endocrin Connect, 3(2):R45-54.

Mazzawi T, et al. (2015) Increased chromogranin A cell density in large intestine of patients with irritable bowel syndrome after receiving dietary guidance. Gastroenterology Research and Practice, Article ID 823897.

Zenker N, Afrin LB. (2015) Utilities of various mast cell mediators in diagnosis mast cell activation syndrome. Blood, 126:5174.

Massironi S, et al. (2016). Chromogranin A and other enteroendocrine markers in inflammatory bowel disease. Neuropeptides, xxx, xxx-xxx.

Skinny

by Lisa Klimas
January 29, 2017

My body is my adversary. I hardly remember a time when that was not the case. Even before I got sick, I struggled to make my body do the things I wanted it to. You can only do that so much before you begin to resent these shells we live in.

I was a small child, very small. I wasn’t four feet tall until eighth grade. That year, I grew a foot, and never again. Throughout elementary school, people commented on how small I was and how little I weighed. I was limber and very nimble; together with my lack of height, these characteristics gave me the body of a gymnast. I did splits and back handsprings and aerial cartwheels in my living room and backyard. I threw tricks during recess. I weighed so little that very little strength was required.

In seventh grade, I acquired the body of a woman overnight. I took ballet classes at that point in a small brown building around the corner from my house. One day, I caught my reflexion in the wall mirrors. I was rounder, with thick legs, breasts and a forming hourglass figure. I was still short but I wasn’t small.

I lamented the loss of my tiny frame but I wasn’t overly concerned with toning or losing weight. I walked a lot and was active if not athletic. In 2000, I started getting a three month birth control injection. In the months that I followed, I gained 26 lbs. I went from being thicker to being fat.

I was very unhappy with my body throughout college and grad school. I worked more than full time and carried a full course load. I picked up better eating habits when I got an apartment but I didn’t have time to exercise.

In 2007, I woke up in the middle of the night and while walking across my living room carpet to the bathroom, I realized my ass was jiggling. It actually stunned me awake. The next morning, I signed up to walk the Breast Cancer 3-day, 60 miles in three days, largely for the fitness aspect of the event. For the next six months, I walked increasing distances 3-4 days a week and did short workouts on the other days. I didn’t change my diet at all except for not drinking coke. I lost 25 lbs and gained a lot of muscle.

The summer of 2007 stands out for me as a time when I was happy with my body. I was still bigger than I wanted to be, but I was actively losing weight and felt much stronger and more able. I went backpacking in Scandinavia and was on strenuous mountain hikes without trouble. I took up rock climbing. I completed the 3-day and continued with the training schedule. Over the next three years, I would walk four more 3-days.

In 2009, I lost most of my hearing. I ended up on high dose oral steroids for a few weeks and quickly gained 20 lbs. My face was squishy and I was swollen everywhere and nothing fit anymore. At the same time, my disease was also accelerating. I still walked and tried to make time for yoga class but I was in a lot of pain and often too exhausted to work out. I gained more weight. And more.

By 2012, I weighed about 165 lbs. I started doing advanced yoga several times a week and was able to lose 10 lbs in about nine months. The following year, I had my colostomy placed and lost 10 more lbs. I was stably 145 lbs until the end of 2013 when I started high dose steroids again along with several other meds known to cause fluid retention and weight gain. I gained 30 lbs in six weeks and then gained a little more. My abdomen was so swollen that I looked nine months pregnant. I had to wear maternity clothes to accommodate my belly.

Decreasing steroids took off some weight but I was still much bigger than I wanted to be. In 2015, I had another GI surgery. I again lost 10 lbs almost immediately. Following the surgery, I was able to do a reconditioning program before I returned to work in order to build up my stamina and physical tolerance for exercise. I was less inflamed than before the surgery and reacting less. I was able to address several smaller concerns that had been on the back burner like vitamin D levels. Together, these changes allowed me to recondition effectively. I could exercise again, making it easier to manage my fitness. (For those interested, I describe my reconditioning program here.)

Over the next 18 months, I lost another 10 lbs. I found long, flat muscles in places I never expected to see. Even as I cursed my body for having this disease, I was happier with how it looked. I had to buy new clothes because even my smallest clothes, saved from previous years, were too big.

Last fall, I started dropping weight, much faster than I should have been. At the same time, I was having fevers, night sweats, and a slew of other symptoms I have written about. I countered the weight loss by eating more but I eventually developed gastroparesis and started throwing everything up. I am now getting some of my calories through 2L of IV fluids daily. I am now getting most of my calories from “nutritional drinks”. (My homemade version is Orgain chocolate protein powder, organic maple syrup, and almond milk.) I am tolerating it but I can’t drink it fast without getting nauseous. I’m not getting much fat in my diet and my body is now showing that.

I took a picture of myself tonight. For the first time, I was unsettled by how I looked. I am getting very thin. I am the smallest I have been as an adult. I can certainly lose more weight before I’m in danger but it was seriously jarring to see myself. I am leaving “you don’t look sick” territory.

So here I am at 3am thinking of ways to gain back weight that I spent years trying to lose. A different kind of adversary.

The Provider Primer Series: Relevance of mast cells in common health scenarios

by Lisa Klimas
January 7, 2017

Symptom	Cough
Role of mast cells	Several mast cell mediators contribute to airway inflammation and subsequent symptoms including cough: • Histamine promotes bronchoconstriction, excessive production of mucus, and airway edema.[i] • Prostaglandin D2 promotes bronchoconstriction, mucus production, and airway edema.[i] • Leukotrienes C4 and D4 and chymase also contribute to mucus production and airway edema.[i] • Tryptase promotes overall increased reactivity of the airway.[i] Chronic airway inflammation, as in asthma, is sometimes associated with increased mast cell population in pulmonary tissues.[i] Mast cells remain activated in inflamed airways.[i]
Impact of condition on mast cells	Mast cell activation can occur as a result of the physical stimuli such as coughing[ii]. Pain can trigger mast cell activation[iii].
Notes regarding condition treatment	Dextromethorphan can trigger mast cell degranulation[iv]. Codeine and derivatives can trigger mast cell degranulation[v]. Beta-2 adrenergic agonists, inhaled and oral steroids, and inhaled cromolyn are frequently used in mast cell patients[vi].
Notes regarding mast cell treatment	Antihistamines, leukotriene receptor antagonists, and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vii] Racemic epinephrine can provide relief of pulmonary symptoms.[viii]
Special considerations for mast cell patients	Chronic dry, unproductive cough sometimes occurs in mast cell patients.[ix] Mast cell patients frequently have reactive airways.[ix] Mast cells can produce and release prostaglandin E2, a mediator that participates in asthmatic inflammation and cough[x]. Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface[x].

Symptom	Sore throat
Role of mast cells	Pain can trigger mast cell activation.[iii]
Impact of condition on mast cells	Mast cell driven nasal congestion can result in postnasal drip can irritate the throat.[ix] Mast cell irritation of the throat can present similarly to infection by Streptococcus spp. or other pathogen. Cultures should be taken to properly evaluate for infection.[ix] Viral, bacterial and fungal infection will activate mast cells through toll like receptors and through perpetuated inflammatory signaling.[xiii]
Notes regarding condition treatment	Acetaminophen is recommended for pain relief in mast cell patients.[iv]
Notes regarding mast cell treatment	Antihistamines and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients	Angioedema of the throat driven by mast cell disease is always a consideration in mast cell patients. If angioedema secondary to mast cell disease impinges upon airway, epinephrine and subsequent anaphylaxis treatments should be undertaken.[vii] Oral allergy syndrome should be considered.[ix]

Symptom	Rash
Role of mast cells	Acute urticaria is usually driven by mast cell and basophil activation through IgE or non-IgE pathways.[xi] Mast cell mediators histamine, leukotrienes and platelet activating factor contribute to itching.[xii]
Impact of condition on mast cells	Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii] Non-mast cell driven conditions causing skin rashes can irritate mast cells in the skin.[xii] Pain can trigger mast cell activation.[iii]
Notes regarding condition treatment	Some -azole antifungals can induce mast cell degranulation.[xiv]
Notes regarding mast cell treatment	Antihistamines and steroids, topical or systemic, and topical cromolyn can provide relief.[xii]
Special considerations for mast cell patients	Mediator release by activated mast cells can produce systemic symptoms.[x] In patients with a history of mast cell disease, mastocytosis in the skin should be considered. o Cutaneous mastocytosis accounts for approximately 90% of mastocytosis cases.[xii] o Cutaneous mastocytosis lesions demonstrate Darier’s sign, a wheal and flare reaction to touch.[xii] o A skin biopsy is necessary to confirm a diagnosis of cutaneous mastocytosis.[xii] o Patients with adult onset cutaneous mast cell lesions are usually later found to have systemic mastocytosis.[xii]

Symptom	Fever
Role of mast cells	Mast cells can produce prostaglandin E2.[x] Mast cells can produce and release several pyrogens, including IL-1α, IL-1β, IL-6, IL-8, TNF, interferon-α, interferon-β, and interferon-γ.[x]
Impact of condition on mast cells	Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface.[x] Pain can trigger mast cell activation.[iii] Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]
Notes regarding condition treatment	NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv] Acetaminophen is generally recommended for use in mast cell patients.[iv]
Notes regarding mast cell treatment	COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]
Special considerations for mast cell patients

Symptom	Earache
Role of mast cells	Mast cells are involved in the transmission of pain stimuli, including nerve pain.[iii] Mast cells are involved in sensorineural hearing loss and tinnitus.[ix]
Impact of condition on mast cells	Pain can trigger mast cell activation.[iii] Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]
Notes regarding condition treatment	NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv] Acetaminophen is generally recommended for use in mast cell patients.[iv] Steroids (local and systemic) can stabilize mast cells.[vi]
Notes regarding mast cell treatment	COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi] Antihistamines can provide relief for vestibular symptoms.[vi]
Special considerations for mast cell patients	Hearing loss, tinnitus and hyperacusis sometimes occur in mast cell patients.[ix] Sensorineural hearing loss of unknown origin has been documented in mast cell patients.[ix] Some mast cell patients also have Ehlers Danlos Syndrome which can cause conductive hearing loss.[ix] Mast cell disease can also cause auditory processing disorder.[ix] Red ears are a common sign of mast cell activation. Sometimes, only one ear is affected.[ix]

Symptom	Stomachache
Role of mast cells	Mast cells are commonly found in the GI tract.[xvi] Mast cell activation is involved in a number of GI conditions, including inflammatory bowel disease, ulcerative colitis and food allergies.[xvi] Mast cell activation can cause chronic diarrhea, pseudoobstruction, obstruction, dysmotility, constipation, nausea, vomiting, and visceral GI pain.[xvi]
Impact of condition on mast cells	GI inflammation can recruit mast cells to inflamed tissues.[xvi] GI inflammation can trigger mast cell mediator release.[xvi] Pain can trigger mast cell activation.[iii] Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]
Notes regarding condition treatment
Notes regarding mast cell treatment	Histamine H2 blockers and PPIs are commonly taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients	Mast cell patients can experience a wide array of severe GI symptoms with or without dense infiltration of GI tract by mast cells.[ix]

[i] Cruse G, Bradding P. (2016). Mast cells in airway diseases and interstitial lung disease. European Journal of Pharmacology 778, 125-138.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1):113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

[viii] Walsh P, et al. (2008). Comparison of nebulized epinephrine to albuterol in bronchiolitis. Acad Emerg Med, 15(4):305-313.

[ix] Afrin LB. (2013). Diagnosis, presentation and management of mast cell activation syndrome. Mast cells.

[x] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[xi] Bernstein JA, et al. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5):1270-1277.

[xii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1):35-45.

[xiii] Sandig H, Bulfone-Paul S. (2012). TLR signaling in mast cells: common and unique features. Front Immunol, 3;185.

[xiv] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells. Pharm Pharmacol, 52(3), 327-331.

[xv] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xvi] Ramsay DB, et al. (2010). Mast cells in gastrointestinal disease. Gastroenterology & Hepatology, 6(12): 772-777.

Take home points: August 2015

by Lisa Klimas
July 14, 2016July 16, 2016

Gastroparesis: Part 1

GP is a condition in which stomach contents do not move into the small intestine in an appropriate time frame without an obvious anatomical reason
GP patients can have severe symptoms, including nausea, vomiting, abdominal pain and bloating
GP can be episodic or chronic
The degree of gastric emptying delay does not impact symptom severity
GP may affect up to 2% of the population
GP is increasing over the last twenty years with no clear reason as to why
Cisapride is effective for treating GP but was removed from the market
GP symptoms are generic and make the cause hard to identify
Idiopathic GP has no clear cause and affects up to 1/3 of GP patients

Gastroparesis: Treatment (Part 2)

Treating dehydration and electrolyte and nutritional deficiencies are key to initial GP management
64% of GP patients do not consume enough daily calories
Vitamins A, B6, C and K, iron, potassium and zinc are often deficient in GP patients
Small meals with low fat and fiber are recommended
Liquids or blended solids often empty normally from stomach
Feeding tubes may be placed if malnutrition is significant
Metoclopramide is approved for GP but use longer than twelve weeks carries risks like dystonia
Domperidone is not approved in US for GP but can be imported through a special FDA program for GP
Medications to increase gastric motility, like erythromycin, are often used
Medications for nausea and vomiting are common, such as ondansetron, scopolamine, draonabinol and tricyclic antidepressions
Nortriptyline and desipramine are tricyclics of choice as amitryptline can cause delayed gastric emptying
Opiates can induce GP so meds like gabapentin, tramadol, tapentadol, pregabalin and nortriptyline are preferred for abdominal pain
Botox injection into pyloric sphincter can increase gastric emptying but doesn’t always improve symptoms
Acupuncture and gastric pacemaker are also options

Gastroparesis: Diabetes and gastroparesis (Part 3)

40% of patients with type I diabetes have delayed gastric emptying
20% of patients with type II diabetes have delayed gastric emptying
In 2004, 26.7% of GP patients had diabetes
Diabetic patients with GP are more likely to have nausa and vomiting as predominant symptoms
GP can hinder effective blood sugar management
High blood sugar is associated with GP and vagus nerve damage
Gastric electric stimulation (gastric pacemaker) works better when GP is caused by diabetes than GP from other causes
Effective GP management improves blood sugar management and A1C level

Gastroparesis: Post-surgical gastroparesis (Part Four)

Surgery is a common trigger for GP
Surgeries that manipulate the stomach are more associated with GP, like gastrectomy, fundoplication or weight loss surgery
Gastric inflammation associated with surgery inhibits GI motility
7.2% of GP cases occur after gastrectomy or fundoplication
Nissen fundoplication is the most common cause of post-surgical GP
A follow up surgery after Nissen fundoplication can sometimes reverse GP
Surgeries that don’t manipulate the stomach can also cause GP, like removal of esophagus, lung transplant, and liver surgery

Gastroparesis: Less common causes (Part Five)

Parkinson disease, multiple sclerosis, muscular dystrophy, myopathy, scleroderma, Sjogrens, polymyositis and stroke can all cause GP.
10.8% of GP cases are associated with connective tissue disorder
Pseudo obstruction syndromes and autonomic neuropathy can occur concurrently with GP
Viral infections can cause acute GP that usually resolves within a year
Spinal cord injury, hypothyroidism, hyperparathyroidism, Addison’s disease and use of opiates or anticholinergics can contribute to GP
GP occurs disproportionately in people who have had their gallbladders removed
- Often, GP does not immediately follow gallbladder removal but can present months or years later
- Gallbladder removal is also associated with conditions that can occur with GP such as chronic fatigue syndrome, fibromyalgia, depression and anxiety
- GP patients who have had gallbladders removed are usually older women who are overweight despite not coming enough calories

Take home points: September 2015

by Lisa Klimas
July 14, 2016July 16, 2016

Naturally occurring mast cell stabilizers: Part 1

Naturally occurring mast cell stabilizers: Part 2

Naturally occurring mast cell stabilizers: Part 3

Naturally occurring mast cell stabilizers: Part 4

Amentoflavone	Ginkgo biloba, St. John’s Wort	Decreases histamine release
Artekeiskeanol A	Artemisa keiskeana	May treat arthritis Decreases mast cell degranulation Decreases production of IL-13 and TNF
Curcimin	Turmeric	Decreases degranulation Decreases production of IL-4 and TNF
Ellagic acid	Strawberries, raspberries, pomegranate, walnuts	Suppresses IgE activation Decreases release of histamine, TNF, IL-6
Emodin	Rhubarb, frangula bark	Decreases IgE degranulation Decreases IgE triggered production of TNF, PGD2, LTC4 Decreases secretion of TNF and IL-6
Epigallocatechin gallate	White and green teas, apples, onions, hazelnuts	Decreases degranulation Decreases LTC4 secretion
Fisetin	Apples, onions, persimmon, strawberries, cucumber	Decreases IgE degranulation Decreased IgE triggered histamine release Decreases production of IL-1b, IL-6, IL-8 and TNF Decreased action of NF-kB, decreased mediator production
Furanocoumarin from Angelica dahurica	Angelica dahurica	Inhibits COX-2 and 5-LO, decreasing production of prostaglandins and LTC4
Genistein	Genista tinctoria	Decreases IgE degranulation Decreases histamine release Nature tyrosine kinase inhibitor
Ginkgetin	Gingko biloba	Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes
Gnetin H	Paeonia aneomala	Resveratrol derived polymer Decreases mast cell degranulation Effective at lower dose than reservatrol Decreases histamine secretion Decreases production of TNF, IL-4, COX-2 and PGE2
Homoisoflavonone	Cremastra appendiculata	Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes Decreases IgE triggered production of TNF and IL-6
Honokiol	Magnolia obovata	Suppresses allergic response and basophil activation
Hydroxytyrosol	Olive oil, olive leaves	Inhibited activation of mast cells at high concentration
Hypothemycin	Hypomyces mushrooms	Interfere with activation of CKIT and IgE receptors, inhibiting mast cell activation Decreases production of IL-4
Kaempferol	Potatoes, squash, cucumbers, peaches, Aloe versa	Decreases IgE degranulation Decreased IgE triggered histamine release Affects estrogen signaling
Luteolin	Celery, carrots, chamomile tea	Prophylactic use of luteolin suppresses activation of mast cells and T cells Decreases IgE degranulation Decreases production of mediators
Magnolol	Magnolia obovata	Suppresses allergic response and basophil activation
Morin	Osage orange, guava	Decreases mast cell degranulation Decreases IgE activation
Myricetin	Walnuts, onions, red grapes	Decreases IgE degranulation Decreased IgE triggered histamine release Decreases production of IL-6 and TNF Decreased action of NF-kB, decreased mediator production
Polydatin		Resveratrol precursor Makes small intestine mucosa less “leaky” and inhibited allergic reaction in intestines Decreases degranulation by up to 65% Decreases histamine in intestinal mucosa and serum Decreases production of IL-4
Quercetin	Red onion, sweet potato, kale	Inhibits production of histamine, prostaglandins, leukotrienes, IL-1b, IL-6, IL-8 and TNF
Resveratrol	Grapes, raspberries, blueberries, peanuts	Directly interferes with degranulation Decreases production of TNF, IL-6 and IL-8
Rottlerin	Mallotus philippensis	Decreases degranulation of airway mast cells Decreases histamine release Suppresses IgE activation
Rutin		Decreases IgE degranulation Decreased IgE triggered histamine release Decreases production of IL-1b, IL-6, IL-8 and TNF Decreased action of NF-kB, decreased mediator production
Scopoletin	Stinging nettle, Japanese belladonna, chicory, passion flower	Decreases production of TNF, IL-6, IL-8 Inhibits NF-kB, affecting mediator production
Selinidin	Angelia keiskei	Inhibits IgE degranulation Decreases production of LTC4 and TNF
Substance	Source	Function
Thunberginol A	Hydrangeae macrophylla	Decreases histamine release Decreases production of TNF and IL-4
Thunberginol B	Hydrangeae macrophylla	Decreases degranulation from IgE or other sources Decreases IgE triggered production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF
Xanthones from purple mangosteen	Garcinia mangostana	Decreases release of histamine, PGD2, LTC4 and IL-6

Role of sex hormones in hereditary angioedema

Gastroparesis: Autonomic nervous system and vagus nerve (Part Six)

ANS controls many involuntary functions including digestion and therefore gastric emptying
The vagus nerve coordinates gastric motility
ANS dysfunction inhibits digestion and motility
GP is common in patients with ANS conditions, like POTS
Treatment of autonomic dysfunction (as in POTS) can sometimes improve GP
Damage to the vagus nerve can cause liquids to move rapidly out of the stomach while solids are retained
Surgery and high blood sugar can damage the vagus nerve
In GP patients, nerve cells are not shaped correctly
83% of GP patients have abnormalities in their stomach biopsies

Gastroparesis: Idiopathic gastroparesis (Part Seven)

35-67% of GP cases are idiopathic (IGP)
IGP affects three times more women than men, especially young and middle-aged women
IGP is more likely in young women who are overweight or obese
Moderate to severe abdominal pain was more frequent in IGP than other types
Nausea, abdominal pain, vomiting, bloating and feeling full are common in IGP
Medications that may be helpful but need investigation include sildenafil, paroxetine, cisapride, tegaserod, clonidine and buspirone

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

by Lisa Klimas
May 5, 2016July 16, 2016

Skin symptoms
Symptom	Mediators	Mechanism
Flushing	Histamine (H1), PGD2	Increased vasodilation and permeability of blood vessels Blood is closer to the skin and redness is seen
Itching	Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF	Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria	Histamine (H1), PAF, heparin, bradykinin	Increased vasodilation and permeability of blood vessels and lymphatic vessels Fluid is trapped inappropriately between layers of skin
Angioedema	Histamine (H1), heparin, bradykinin, PAF	Increased vasodilation and permeability of blood vessels and lymphatic vessels Fluid is trapped inappropriately between layers of tissue

Respiratory symptoms
Symptom	Mediators	Mechanism
Nasal congestion	Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4	Increased mucus production Smooth muscle constriction
Sneezing	Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4	Increased mucus production Smooth muscle constriction
Airway constriction/ difficulty breathing	Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF	Increased mucus production Smooth muscle constriction

Cardiovascular symptoms
Symptom	Mediators	Mechanism
Low blood pressure	Histamine (H1), PAF, PGD2, bradykinin	Decreased force of heart contraction Increased vasodilation and permeability of blood vessels Impact on norepinephrine signaling Change in heart rate
Presyncope/syncope (fainting)	Histamine (H1), histamine (H3), PAF, bradykinin	Increased vasodilation and permeability of blood vessels Decrease in blood pressure Dysfunctional release of neurotransmitters
High blood pressure	Chymase, 9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A	Impact on renin-angiotensin pathway Impact on norepinephrine signaling Tightening and decreased permeability of blood vessels
Tachycardia	Histamine (H2), PGD2	Increasing heart rate Increasing force of heart contraction Impact on norepinephrine signaling
Arrhythmias	Chymase, PAF, renin	Impact on renin-angiotensin pathway Impact on norepinephrine signaling

Gastrointestinal symptoms
Symptom	Mediators	Mechanism
Diarrhea	Histamine (H1), histamine (H2), bradykinin, serotonin	Smooth muscle constriction Increased gastric acid secretion Dysfunctional release of neurotransmitters
Gas	Histamine (H1), histamine (H2), bradykinin	Smooth muscle constriction Increased gastric acid secretion
Abdominal pain	Histamine (H1), histamine (H2), bradykinin, serotonin	Smooth muscle constriction Increased gastric acid secretion Dysfunctional release of neurotransmitters
Nausea/vomiting	Histamine (H3), serotonin	Dysfunctional release of neurotransmitters
Constipation	Histamine (H2), histamine (H3), serotonin (low)	Dysfunctional release of neurotransmitters

Mast cells in the GI tract: How many is too many? (Part eight)

by Lisa Klimas
January 11, 2016July 16, 2016

One study assessed whether mast cell count would be influenced depending on which part of the organ biopsies were taken from. While the difference in count was not large, it is worth considering that these counts all straddle the cut off of 20 mast cells/hpf. This means that patients with the same GI symptoms could have biopsies with over or under 20/hpf depending on the site of the biopsy. See Table 24 for details.

Table 24: Effect of sampling site on mast cell count/hpf in colon of chronic diarrhea patients
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC), toluidine blue
Rectum	Sigmoid	Descending colon	Transverse colon	Ascending colon	Cecum
20.5±5	18.3±3.5	22.6±3.9	20.7±4.9	25.5±6.7	22.1±4.9

The same paper also looked at effect of season on mast cell count. There was no significant difference, but again, the range of biopsies in each season straddles the 20/hpf line. See Table 25 for details.

Table 25: Effect of season on mast cell count in colon of diarrhea patients
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC), toluidine blue
Spring	Summer	Fall	Winter
20.6±4.7	24.2±4.9	19.5±3.9	20.3±4.9

The most telling portion of this study compared mast cell counts when using a simple stain (toluidine blue) and when using IHC (antibody for tryptase) to find mast cells in biopsies. Mast cells are not easy to see on biopsy. They require special stains, and even then, they are hard to see. Immunohistochemistry (IHC) uses antibodies to identify markers on cells that are easier to see with a microscope. It is not uncommon for unfamiliar doctors to refuse the use of IHC testing (which usually includes CD117, CD25, CD2 or tryptase) in lieu of commonly available stains in the lab. However, even stains that visualize mast cells are inferior to IHC methods. In biopsies taken from all parts of the colon, toluidine blue staining showed less than half of the mast cells visualized using IHC for tryptase. This means that when IHC testing isn’t ordered, counts reported by simple staining are much lower than the true count. See Table 26 for details.

Table 26: Comparison of mast cell count in biopsies stained with toluidine blue and with tryptase antibody (IHC)
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC) and toluidine blue
Staining method	Rectum	Sigmoid	Descending colon	Transverse colon	Ascending colon	Cecum
IHC	20.5±5	18.3±3.5	22.6±3.9	20.7±4.9	25.5±6.7	22.1±4.9
Toluidine blue	8.5±0.7	6.8±1.2	10.3±4.2	10.3±3.5	12.5±5	8.1±2.9
% of cells identified by IHC seen by toluidine blue staining	41%	37%	46%	50%	49%	37%

There are other factors that contribute to lack of consensus in mast cell counts in GI tissue. One of the biggest causes is that not all labs use standard size high powered fields. HPF is usually 0.25mm², but it is not uniform throughout the research world. Many papers don’t even provide the size of their high powered fields. More than that, many papers report mast counts per mm² without providing conversion factors so it’s not always possible to compare results from one paper to another. There were some papers I wanted to use for this series that I couldn’t because I couldn’t be sure that I could convert their mast cells/mm² confidently to mast cells/hpf.

Together with the fact that number of hpf counted, methods of biopsy slide preparation, stains and IHC antibodies are variable, it is hard to get a real understanding of whether the cut off of 20 mast cells/hpf is meaningful. It is my finding that there are a number of conditions that cause mast cells/hpf to be higher than controls in an experiment. It is also my finding that in some experiments, control subjects have baseline mast cell counts over 20 mast cells/hpf. It is reasonable to assume that inflammatory GI conditions can cause mast cell hyperplasia. But the fact that chronic urticaria patients often have mast cell counts higher than control subjects is also telling. It speaks to the fact that an allergic process can elevate mast cell counts in a space where there is no appreciable symptomology. If patients have reactions to “pseudoallergens” as described in that paper, then it is possible that these reactions could drive the increase in mast cell count in the GI tract. If this is true, then the many mast cell patients who have “pseudoallergen” responses could see an increase in GI mast cell burden as a result of their mast cell disease.

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea. Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al. Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

Mast cells in the GI tract: How many is too many? (Part seven)

by Lisa Klimas
January 9, 2016July 16, 2016

The 2014 Doyle paper provides mast cell counts in colon biopsies for healthy controls, MCAS, and IBS. Mast cells were identified using antibodies for tryptase, CD117, CD25 and CD30 (IHC). Mast cells were counted in both one HPF in the densest portion of the slide and in five HPF and averaged. In the densest portion of the slide, mast cell counts were higher in 1 HPF than in the average of 5 HPF. Differences in methodology such as this can contribute to lack of consensus on what constitutes too many mast cells. See Table 21 for details.

Table 21: Comparison of mast cell count in 1 HPF and in the average of 5 HPF
Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.
Microscopy method: 400x magnification, mast cells counted in 1 hpf
Visualization: IHC for tryptase, CD117, CD25 and CD30
HPF	Control group A: Healthy controls		Control group B: MCAS		Control group C: IBS
HPF	Average	Range	Average	Range	Average	Range
Average of 5 hpf	19 mast cells/hpf	7-39 mast cells/hpf	20 mast cells/hpf	12-31 mast cells/hpf	23 mast cells/hpf	9-45 mast cells/hpf
1 hpf	26 mast cells/hpf	11-55 mast cells/hpf	28 mast cells/hpf	14-48 mast cells/hpf	30 mast cells/hpf	13-59 mast cells/hpf

Other papers also investigated factors that could contribute to differences in mast cell counts. The 2015 Sethi paper evaluated differences in GI mast cell counts between men and women. Women had marginally higher counts in both IBS and control groups. See Table 22 for details.

Table 22: Difference in mast cell count between men and women with chronic diarrhea and asymptomatic controls
Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: CD117 (IHC)
Sample type	Study group: Women		Study group: Men		Control group: Women		Control group: Men
Colon	Average	Range	Average	Range	Average	Range	Average	Range
	30 mast cells/hpf	27-34 mast cells/hpf	27 mast cells/hpf	24-31 mast cells/hpf	24 mast cells/hpf	22-37 mast cells/hpf	21 mast cells/hpf	19-24 mast cells/hpf
	Diffuse scattered cells, no clusters.		Diffuse scattered cells, no clusters.		Diffuse scattered cells, no clusters.		Diffuse scattered cells, no clusters.

One paper looked at the difference in mast cell count in the rectum of healthy patients over the age of 55 and under. Please note that these counts were made using a much lower magnification than other papers in this series, so mast cell counts are not directly comparable. Mast cells were identified using antibodies to tryptase (IHC). See Table 23 for details.

Table 23: Differences in GI mast cell count in healthy patients over and under 55 years of age.
Dunlop SP, et al. Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.
SPECIAL NOTE: THESE COUNTS WERE MADE AT HALF THE MAGNIFICATION OF OTHER PAPERS IN THIS SERIES. THESE MAST CELL COUNTS ARE NOT DIRECTLY COMPARABLE TO OTHER STUDIES.
200x magnification, number of hpf not explicitly stated, assumed mast cells counted in 1 hpf
Visualization: Tryptase (IHC)
Sample type	Study group: Healthy, over 55 years old		Study group: Healthy, under 55 years old		Control group B: No control group
Rectum	Average	Range	Average	Range	Average	Range
	40.5 ± 2.4 mast cells/hpf		51.7 ± 4.1 mast cells/hpf		N/A	N/A