Skip to content

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.

Regulation of mast cells by IgE and stem cell factor (SCF)

Mast cells are regulated by two dominant mechanisms. The first is the allergic response via the high affinity IgE receptor. This receptor is called FcεRI. When an IgE molecule binds to this receptor, it triggers the release of calcium in pockets inside the cells, causes the cells to take up more calcium from outside the cell, and changes the cell membrane so that it can degranulate and secrete mediators. There are a number of other things that can affect the strength of the response triggered by FcεRI.

The second mechanism is the survival and activation response when stem cell factor (SCF) binds to the CKIT receptor (also called KIT). SCF is the primary growth and survival factor in non-neoplastic mast cells. In the absence of mast cell disease, it is absolutely required for survival. SCF also attracts mast cells and enhances degranulation from the FcεRI (IgE) receptor, production of cytokines and movement of mast cells from one place to another.

When SCF is increased in tissues, it increases the amount of mast cells there, how long they live and what roles they play. It also increases mast cell responsiveness. In some instances, SCF can directly cause degranulation with IgE involvement.

Despite understanding the importance of SCF, it is not well understood what happens after SCF binds to the CKIT receptor. We know that it increases survival and proliferation, but it’s not clear how. It is possible that the concentration of SCF or CKIT may play a role.

In tissues, mast cells often exist as a part of a membrane, and SCF is important in mast cell adhesion to other cells. When SCF is part of that membrane, it can increase histamine and eotaxin production in mast cells.

Monomeric IgE is IgE that is not bound to an allergen. In the presence of SCF, monomeric IgE can directly cause release of histamine, LTC4 and IL-8. It also makes mast cells more reactive.   When monomeric IgE binds to the FcεRI (IgE) receptor without SCF present, it causes production of IL-6 but not degranulation. However, IL-6 promotes mast cell survival.

References:

Cruse, G., Bradding, P. Mast cells in airway dieases and institial lung disease. Eur J Pharmacol (2015).

River, K., Gilfillian, A.M. Molecular regulation of mast cell activation. J Allergy Clin Immunol 2006, 117, 1214-1225.

Gilfillian, A.M., Beaven, M.A. Regulation of mast cell responses in health and disease. Crit Rev Immunol 2011, 31, 475-529.

 

November 2014: Post summaries and take home points

Food allergy series: Atopy, risk factors and frequency

  • Food allergy generally refers to IgE mediated reactions in literature
  • Other reactions can cause severe food reactions via different mechanisms
  • Food allergy reacts to specific allergen following skin or mucosal contact (mouth, GI tract)
  • Sensitization is when your body makes IgE to something.
  • Allergy is when your body makes IgE to something and that thing makes you sick.
  • Atopy is the tendency of a person to develop allergic diseases like asthma.
  • The term “allergic march” describes progressive accumulation of atopic conditions starting in the first year of life.
  • Allergic march usually begins with atopic dermatitis and progresses to allergic rhinitis, asthma, and food allergy.
  • Severe eczema developed in the first six months of life is associated with increased risk of peanut, milk and egg allergies.
  • Most food allergies are due to egg, cow’s milk, wheat, soy, shellfish, peanuts and tree nuts.
  • 4% of children with food allergies have multiple food allergies.
  • Children with multiple food allergies are most likely to have severe reactions.
  • Adolescents ages 14-17 are more likely to have severe reactions.
  • Peanut, cashews, walnuts and shellfish allergies are most likely to be severe.
  • Largest studies on food allergy use patient reported information which is not the most reliable.
  • Many people eliminate foods from their diets based upon suspicion of allergy. This is usually unnecessary.
  • 89% of patients with atopic dermatitis were shown to have no reactions to suspect foods on oral challenge.
  • 4% of US households had children with multiple food allergies.
  • 3% of US households had children with history of severe allergic reaction.
  • In Canadian households, 8% of people have food allergies.
  • In Australia, 3% of children are allergic to peanuts and 8.9% are allergic to raw eggs.
  • Risk factors for food allergies include:
  • Atopy
  • Low vitamin D
  • Reduced consumption of omega-3 polyunsaturated fatty acids
  • Reduced consumption of antioxidants
  • Increased use of antacids
  • Obesity
  • Increased hygiene
  • Delaying exposure to common allergens
  • Family history of food allergies
  • Specific HLA profiles
  • Male children are more likely to develop food allergies.
  • Black children are most likely to develop food allergies, followed by Asian children, then White children.
  • Children of immigrants in the US are at higher risk than children of American born parents.
  • People living in households earning more than $50,000/yr are more likely to be diagnosed with food allergies.
  • Childhood allergies to milk, egg, wheat and soy are more likely to resolve.
  • Childhood allergies to peanut, tree nut, fish and shellfish are more likely to persist.

MTHFR, folate metabolism and methylation

  • MTHFR stands for methylenetetrahydrofolate reductase.
  • MTHFR is an enzyme involved in folate metabolism.
  • If there is not enough MTHFR, your body cannot break down enough folate.
  • Some folate broken down by your body is used to methylate DNA.
  • DNA methylation is one of the ways your body regulates which genes are turned on and off.
  • A single nucleotide polymorphism (SNP) is a mutation in DNA sequence at one place.
  • SNPs are very common.
  • There are multiple known SNPs that can occur in the MTHFR gene.
  • The two SNPs of interest in the MTHFR gene are called C677T and A1298C.
  • C677T mutation is found in 10% of North Americans, most commonly Hispanics and those of Mediterranean descent.
  • Having two copies of the C677T (called “being homozygous”) can cause mild MTHFR deficiency and result in too much homocysteine.
  • Increased homocysteine has been studied in connection to many conditions but the results are inconclusive.
  • A1298C mutation is not known to elevate homocysteine.
  • A1298C mutation may cause deficiency of BH4, which is important in neurotransmission and formation of nitric oxide.
  • There is no strong support in peer reviewed literature for the association of C677T or A1298C with disease. Many studies contradict each other.
  • There is no known link between MTHFR mutations and mast cell disease.

DNA methylation: How it works

  • DNA methylation is one of the ways your body controls which genes are turned on and off.
  • Methylation is important in cancer.
  • Methylation of tumor suppressor genes causes them to be turned off, resulting in cancers.

Mast cells, heparin and bradykinin: the effects of mast cells on the kinin-kallikrein system

  • The kinin-kallikrein system is a group of hormones that affect inflammation, blood pressure, coagulation and pain perception.
  • It also affects the cardiovascular system, including cardiac failure.
  • This system produces bradykinin.
  • Bradykinin has many functions, including GI contraction, bronchoconstriction, induction of cell proliferation, collagen synthesis and release of many molecules.
  • Bradykinin causes blood vessels to dilate, decreasing blood pressure.
  • Bradykinin affects sodium excretion from the kidneys, further decreasing blood pressure.
  • Bradykinin opposes the action of angiotensin II, which increases blood pressure.
  • Mast cells release bradykinin and molecules to make it.
  • Mast cells also release heparin, which can initiate bradykinin formation.
  • Too much bradykinin causes angioedema.
  • Mast cell degranulation occurs with physical trauma in part due to formation of bradykinin.
  • Bradykinin induces release of histamine, serotonin and other molecules.

Biphasic anaphylaxis

  • Monophasic anaphylaxis is one episode of anaphylaxis symptoms.
  • Biphasic anaphylaxis is a second episode of anaphylaxis symptoms after resolution of symptoms.
  • Late onset anaphylaxis occurs several hours after exposure to trigger.
  • Protracted anaphylaxis is a long episode of anaphylaxis symptoms despite treatment.
  • Higher doses of corticosteroids may decrease incidence of second phase.
  • Studies on frequency of biphasic anaphylaxis differ on rate of incidence, but most report around 20% of patients have biphasic anaphylaxis.
  • Second phase can occur over a day after the first.
  • Biphasic patients had longer lasting initial anaphylaxis reactions.
  • Biphasic patients statistically receive less epinephrine for the initial reaction, which may result in the second reaction.
  • Delay in administration of epinephrine, inadequate dosing of epinephrine and need for large doses of epinephrine make biphasic anaphylaxis more likely.
  • Previous cardiovascular history, older age and use of beta blockers are risk factors for biphasic reactions.
  • Oral ingestion of trigger makes biphasic reactions more likely.
  • Not clear if mastocytosis patients are more likely to experience biphasic reactions.

MCAS: Respiratory symptoms

  • Throat symptoms are common in MCAS.
  • MCAS reactions can cause inability to swallow or breathe due to angioedema.
  • Breathing difficulty requires epinephrine.
  • Low level difficulty of breathing (feeling like you can’t get a deep breath) is the most common MCAS respiratory symptom.
  • Chest x-ray and pulmonary function testing are usually normal in MCAS patients.
  • Prostaglandin D2 is a potent bronchoconstrictor.
  • Allergic asthma is not uncommon in MCAS.

Fragrance allergy

  • Inhalation can cause anaphylaxis.
  • There have been cases of patients who can ingest a food but react to inhalation, such as Baker’s asthma.
  • Fragrance is one of the top five allergens in North American and European countries.
  • Fragrance allergy can cause skin, eye and respiratory problems.
  • Perfume can cause asthma and other respiratory problems through an unclear mechanism.
  • A significant portion of the population reacts adversely to scented products, even when worn by others.
  • 5% of general population found scented products on others to be irritating.
  • 19% had symptoms from exposure to air fresheners.
  • 9% had symptoms from exposure to scented laundry products.
  • Essential oils can cause allergic reactions regardless of the purity.
  • Some essential oils have been tied to severe allergic reactions, such as clove oil.
  • Oils of citrus fruits liberate histamine and cause mast cell symptoms.
  • In mast cell patients, scents can cause severe full body reactions that are potentially life threatening or fatal.

MCAS: Pain

  • MCAS patients may experience many types of pain.
  • Bone pain, osteopenia and osteoporosis are common in MCAS.
  • Joints and soft tissues are often painful.
  • Mast cells are involved in chronic lower back pain and complex regional pain syndrome.
  • Serotonin can amplify pain signals in chronic pain.
  • Increased serotonin and mast cell counts are found in some patients with chronic abdominal pain.
  • 95% of body serotonin is found in the peritoneal cavity.
  • Tricyclic antidepressants inhibit serotonin release and are sometimes used for abdominal pain.

 

 

 

 

 

 

 

 

 

Mast cells in vascular disease: Part 3

Aneurysms are formed when elastic tissue is degraded by proteases and MMPs; the vessel is thinned due to smooth muscle loss; and the endothelium is broken down, resulting in inflammation. There is a significant body of evidence linking aneurysm formation and growth to mast cell activity.

A number of studies have found that mast cells are present in larger numbers in vasculature near aneurysms. Mast cells are increased in cerebral arteries of patients who died from subarachnoid hemorrhage. In particular, mast cell number is higher in arteries close to the rupture site. Mast cell count has been linked previously to aneurysm instability. Another study found that activated mast cells were increased in the aortas of patients who died from abdominal aortic aneurysms. Increased mast cells are also found in ascending aortic aneurysms. Mast cell density is a predictor for occurrence of ascending aortic aneurysm.

Chymase activity has been heavily implicated in aneurysm physiology. One study found that levels of angiotensin II were unlikely to induce development of aneurysm, but that degradation of the vessel by chymase may weaken the aneurysm and increase risk of rupture. Increased chymase activity was found in an additional fourteen patients having aortic aneurysms repaired. In thoracic aortic aneurysm patients, chymase positive mast cells were found in inflamed areas. Chymase may participate in the generation of reactive oxygen species. In abdominal aortic aneurysm samples, most players in the renin-angiotensin system, including chymase and cathepsins, are increased.

Serpin A3, a protease inhibitor, normally regulates activity of elastase, chymase and cathepsin G. It is thought that deficiency of this molecule may worsen damage caused by chymase.

Mast cell proteases, like tryptase and chymase, may be involved in the formation of aneurysms. Erosion of the endothelium occurred in the thrombosed region of the vessel, followed by decreased oxygen supply to the underlying vessel. Tryptase and chymase may participate in rupture of the vessel and intravascular hemorrhage. Adrenomedullin, a mast cell mediator, is found to be strongly expressed in mast cells to local to aneurysms. Adrenomedullin suppresses formation of the extracellular matrix.

Serum tryptase levels in abdominal aortic aneurysms correlated well with growth of aneurysm as well as risk of complications during repair. Tryptase deficient mice were completely protected against developing this type of aneurysm. Tryptase deficiency reduced expression of cathepsins, as well as activation of endothelial cells and movement of monocytes. Tryptase induces release of cathepsins that trigger apoptosis, so this may be a mechanism.

5-lipoxygenase is the enzyme that drives leukotriene formation. Mice deficient in this molecule were protected against aneurysm formation. They also had less inflammation and apoptosis, lower IL-6 and IFN-γ. Mast cell degranulation augmented aneurysm formation while mast cell stabilizer cromolyn decreased it. Another study found that treatment with tranilast, another mast cell stabilizer, decreased the diameter of the aorta.

Leukotriene C4 and 5-lipoxygenase are increased in patients with abdominal aortic aneurysms, but leukotriene B4 is not. Leukotrienes increase release of MMPs and encourage matrix degradation. Leukotrienes may be a therapeutic target to slow aneurysm progression.

References:

Kennedy, Simon, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53-65.

Bot, Ilze, et al. Mast cells: Pivotal players in cardiovascular diseases. Current Cardiology Reviews, 2008, 4, 170-178.

 

Phantom

I have always been fascinated by both the human body and the diseases that affect it. When I was about ten years old, my parents bought me a medical dictionary. I read it cover to cover. I wrote little stories about people with Legionnaire’s Disease and Tetrology of Fallot, describing the symptoms and treatments in vivid detail.

It was in this dictionary that I first read about phantom pain. It always made a weird sort of sense to me. Bodies are creatures of habit, just like us. Of course your body expects to have all of the parts it started with. Of course your brain would assume it was merely misinterpreting signals when suddenly a limb was missing. The alternative was too awful to consider.

It never occurred to me that the body could experience phantom pain from a part of the body that was never supposed to exist. As soon as my epidural line was pulled five days post-op, I started having severe sporadic pain where my stoma used to be. It was distinct from the other pains – the burning in the lower colon, the sharpness in the rectum, the soreness near the incisions.

This was something different. It felt like when my body tried to pass stool through the stoma, but couldn’t because of an obstruction. It was the same exact same sensation. My body remembers the route of a path that should never have been there to begin with.

I lived 29 years without an ostomy. In the two years that I had it, I believed it was the best solution for me, and for most of that time, I believed that I would always have it. The only way to survive was a radical acceptance of this defect. I told myself that this was the best option for my body and I made myself believe it. I believed it so much that even my body was convinced.

I still have a wound where my stoma was. It is closing slowly. Mostly the pain is manageable; I know it will never really go away. Several times a day, I feel my body mimic the pressure of an obstruction behind the stoma, the twisting and lines of pain spiderwebbing into my lower back. The pain isn’t real, but my brain won’t believe it.

Phantom pain is notoriously resistant to pain medication. One of the better options is the use of psychological “tricks” to convince your body that it is still intact. I am thinking about how to do this. But I don’t know which version of my GI tract my brain thinks is real.

 

Food allergy series: Take home points

Food allergy series: Food related allergic disorders

There are many types of allergic diseases caused by food.

 

Oral allergy syndrome:

  • IgE reaction.
  • Causes itching and swelling in the mouth and sometimes the throat.
  • Less than 2% of cases progress to anaphylaxis.
  • Your body mistakes certain raw fruits and vegetables for pollens and reacts.
  • Cooked foods are usually safe in patients with OAS to raw foods.

Asthma and rhinitis:

  • IgE mediated.
  • Caused by inhaling food protein.
  • Most common in infants and children.
  • Can affect adults in specific work environments, like bakeries.
  • Most commonly induced by the eight major food allergens: egg, milk, wheat, soy, peanut, tree nuts, fish and shellfish.

Urticaria and angioedema:

  • IgE mediated.
  • From ingestion or skin contact.
  • Food ingestion causes 20% of acute urticaria cases and 2% of chronic urticaria cases.
  • More common in children.
  • Usually due to eight major allergens.

GI hypersensitivity:

  • IgE mediated.
  • Immediate vomiting in response to major food allergens.

Food associated, exercise induced anaphylaxis:

  • IgE mediated.
  • Ingestion of food in close time proximity to exercising.
  • Exercise may affect the way the GI tract absorbs and digests allergens.
  • Wheat, shellfish and celery most common to provoke this reaction.

Delayed food-induced anaphylaxis to meat:

  • IgE mediated.
  • Occurs several hours after eating.
  • Body makes antibodies to carbohydrate a-gal.
  • A tick bite can cause the body to make these antibodies.
  • Beef, pork and lamb cause reactions.

Atopic dermatitis:

  • IgE and delated cell mediated reactions.
  • 35% reactions in children due to food.
  • May be due to food reactive T cells in the skin.
  • Egg and milk most common.
  • Usually resolves on its own.

 

Eosinophilic GI disease:

  • IgE and delated cell mediated reactions.
  • Due to eosinophil driven inflammation.
  • Can cause difficult or painful swallowing, weight loss, obstruction and edema.
  • Elimination diets are first line treatments.
  • Endoscopy is diagnostic.

FPIES:

  • Not due to IgE.
  • Usually found in infants.
  • Exposure to food proteins causes chronic vomiting, diarrhea, low energy and poor growth.
  • Cow’s milk, soy, rice and oat are most common offending foods.
  • Cells are more responsive to TNFa and less responsive to TGFb.
  • Usually resolves with age.

Food protein induced allergic proctocolitis:

  • Not due to IgE.
  • Causes mucousy, bloody stools.
  • In response to breast milk containing allergen.
  • Treated by removing food from mother’s diet.

 

Heiner Syndrome:

  • Not due to IgE.
  • Occurs in infants.
  • Triggered by milk, may be a milk specific IgG reaction.
  • Causes pulmonary infiltration, upper respiratory symptoms, iron deficiency anemia and failure to thrive.

Celiac disease:

  • Not due to IgE.
  • Autoimmune disease causes malabsorption and enteropathy.
  • Caused by reaction to gliadin, gluten protein.
  • Can cause bone abnormalities, IgA deficiency, and other issues.
  • Can present at any age.
  • Is lifelong.

Allergic contact dermatitis:

  • Not due to IgE.
  • Eczema in response to metals in foods.
  • Mostly adults.

 

 

 

 

 

 

 

 

 

December 2014: Post summaries and take home points

Food allergy series: Risk factors for developing food allergies

  • Genetics is a factor in development of food allergies.
  • Poor skin integrity makes food allergies more likely.
  • Children with peanut or tree nut allergies usually react on the first ingestion.
  • Household peanut exposure is a risk factor for peanut allergy in infants.
  • Not clear if maternal diet while gestating can affect food allergies.
  • Low vitamin A and low vitamin D are risk factors.
  • Sun exposure and vitamin D deficiency may be connected to food allergies.
  • Hygiene hypothesis posits that changes in hygiene and cleaning has caused immune changes that may lead to allergies.
  • Gut microbiota also important in food allergies.

Food allergy series: FPIES (Part 1)

  • FPIES is the most severe GI food hypersensitivity that is not IgE mediated.
  • Thought to be caused by a delayed allergic pathway.
  • Causes profuse, repetitive comiting, diarrhea, acute dehydration, lethargy and weight loss.
  • Vomiting usually occurs 1-3 hours after eating offending food.
  • Vomiting is seen in 100% of cases.
  • Diarrhea is seen in 24% of cases.
  • Can cause low blood pressure and hypothermia.
  • Chronic symptoms can develop if food is not avoided.
  • About 75% of patients look seriously ill.
  • 15% have blood pressure low enough to require hospitalization.
  • FPIES usually onsets between 1-3 months of age, but can be as late as 12 months.
  • Symptoms usually occur 1-4 weeks after introducing cow’s milk or soy.
  • About 30% later develop atopic conditions.
  • 20% have family history of food allergies.
  • 80% react to more than one food.
  • Usually improve after beginning casein hydrolysate based formula.

Food allergy series: FPIES (part 2)

  • FPIES is diagnosed clinically.
  • Endoscopy and biopsy is often performed to rule out other conditions.
  • GI tract of FPIES patients shows inflammatory changes, such as ulceration and bleeding.
  • Baseline intestinal absorption is usually normal.
  • Food specific IgE is not usually present.
  • FPIES is managed with diet.
  • Exclusive breastfeeding can be protective against FPIES.
  • Oral food challenges require significant precautions and medical supervision.
  • Challenges are recommended every 18-24 months in asymptomatic patients.
  • 60% of FPIES cases resolve by three years of age.
  • In the US, only 25% of cases resolve by three years of age.
  • Most FPIES patients have some form of atopic disease.
  • Some patients may change from an FPIES type reaction to an IgE allergy type reaction.
  • Prevalence is different in different populations.
  • Median age for resolution of FPIES depends on the food and ranges from 4-7 years of age.
  • FPIES overwhelmingly affects very young children.
  • In very rare cases, older children and adults develop FPIES to fish or shellfish.

Food allergy series: Eosinophilic gastrointestinal disease (Part 1)

  • Eosinophilic gastrointestinal disease (EGID) is when eosinophils cause disease in the GI tract.
  • Eosinophils are white blood cells with similar functions to mast cells.
  • Eosinophils fight infections and participate in allergic response.
  • Eosinophils can degranulate.
  • Many GI conditions can elevate eosinophils in the GI tissue.
  • No consensus on what is a high eosinophil count/hpf.
  • Eosinophilic gastroenteritis can affect any part of the GI tract, but usually the stomach and small intestine.
  • Eosinophilic gastroenteritis causes swelling of the Gi tract, eosinophils in the tissue and ulcerations.
  • 50-70% of eosinophilic gastroenteritis is thought to be from allergic reactions.
  • The reason for eosinophilic gastroenteritis is not clear.
  • Eosinophilic esophagitis is 15 or more eosinophils/hpf in at least one field.
  • Eosinophilic esophagitis can be allergic or not.
  • Eosinophilic colitis is a rare condition with sudden onset colon inflammation with eosinophil infiltration that often spontaneously resolves.
  • Eosinophilic enteritis is limited to the small intestine.
  • Allergic proctocolitis affects rectum and/or colon of children under the age of 2.
  • Allergic proctocolitis can be the result of food allergy, most often soy or cow’s milk.

Food allergy series: Eosinophilic gastrointestinal disease (Part 2)

  • There are many conditions that can cause eosinophils to be increased in the GI tract.
  • Allergy associated colitis is when eosinophils aggregate in the small and large intestines as the result of an allergic reaction.
  • Hypereosinophilic syndrome is when people have too many eosinophils in the blood. Rarely, this causes eosinophils to become elevated in the colon.
  • Crohn’s disease causes inflammation of the digestive tract. Eosinophils in the GI tract can be elevated due to inflammation.
  • Ulcerative colitis causes inflammation of the colon. Eosinophils can be elevated in the colon due to inflammation.
  • Collagenous colitis causes inflammation of the colon and rectum. Eosinophils can be elevated. It may occur due to drug reactions.
  • Lymphocytic colitis causes inflammation of large portions of the colon. Eosinophils can be elevated in the mucosal layer.
  • Autoimmune colitis is when autoimmune patients experience colon inflammation. Eosinophils and mast cells are usually found together in affected tissue.
  • Graft versus host disease is a complication of a bone marrow transplant. Eosinophils can be elevated, including in the GI tract.
  • Peripheral/intestinal T cell lymphoma is a cancer that usually affects the small intestine. Eosinophils infiltrate the affected tissue.

Food allergy series: Eosinophilic gastrointestinal disease (Part 3)

  • 70% have family history of allergies
  • 10% have immediate family member with EGID
  • Can cause abdominal pain, GI dysmotility, vomiting, diarrhea, trouble swallowing, anemia, low blood protein and failure to thrive
  • Can cause malabsorption
  • EGID patients are very sensitive to foods. Eggs, milk and fish are most common problem foods.
  • Elimination diets are mainstays of treatment
  • Complete resolution often seen with elemental amino acid diet
  • Reintroduction of foods is not usually tolerated
  • Steroids effective but don’t produce lasting results
  • Mast cells often increased in EGID biopsies
  • Current treatment options not great

Food allergy series: Eosinophilic esophagitis (Part 1)

  • EoE patients are three times more likely to be male than female
  • Most patients have history of atopic disease
  • Usually presents in childhood or after third decade of life
  • Adults tend to have trouble swallowing, food impaction and upper abdominal pain
  • Children have less specific symptoms, including vomiting, abdominal and chest pain
  • 50-60% have at least one atopic condition
  • 15-43% have IgE mediated food allergies, are at greater risk for food induced anaphylaxis
  • No consensus on how many eosinophils/hpf is high

Food allergy series: Eosinophilic esophagitis (Part 2)

  • Endoscopy with biopsy is only reliable diagnostic method
  • May look normal by eye, so multiple biopsies should be taken
  • Mast cells are increased in EoE more than in GERD
  • Other tests rule like esophageal manometry, pH testing and barium swallows can help rule out other conditions
  • Important to exclude GERD
  • 40-50% EoE patients have increased in blood eosinophils
  • When EoE is effectively treated, blood eosinophil count decreases
  • Patients with EoE are found to have overexpression of several proteins
  • Other genetic links have been found

Food allergy series: Mast cell food reactions and the low histamine diet

  • Minimizes histamine in food consumed
  • Histamine from outside sources can induce mast cell degranulation
  • Common problem foods for mast cell patients, like alcohol, vinegar and aged cheeses, are high histamine and cause degranulation
  • There are many different versions of this diet. I use this one.
  • Avoid fermented foods, preservatives, dyes, leftovers, anything overly ripe, canned and pickled products
  • Recommends strict adherence for four weeks to determine if it works
  • Not all recipes labelled low histamine are low histamine

Food allergy series: Eosinophilic esophagitis (part 3)

  • Treatment first rules out GERD or PPI responsive esophageal eosinophilia by treatment with PPIs for 8-12 weeks
  • Some patients have primary EoE and secondary GERD
  • Dietary management is the cornerstone of EoE treatment
  • Dietary management is very effective in children, can achieve remission
  • Food tolerance is unlikely to be achieved even with long erm elimination
  • Steroids effective, but do not produce lasting benefits
  • Fluticasone and oral viscous budesonide effective in studies
  • Cromolyn has no clear benefit for EoE
  • Leukotriene receptor antagonists like Singulair might help, not clear
  • 11-55% of EoE patients suffer food impaction and require emergency intervention
  • Esophageal rings are common in EoE patients
  • Strictures larger than 1 cm in 11-31% of adults with EoE
  • Esophageal perforation can occur and may require surgery
  • Esophageal cancer and generalized EGID are not known to result from progression of EoE
  • Esophageal dilation is sometimes to treat difficulty swallowing and impaction

Food allergy series: Eosinophilic colitis

  • Can occur secondarily to many conditions, such as liver transplant and scleroderma
  • Less than 100 cases of primary eosinophilic colitis reported in literature
  • Experience lower GI symptoms, such as abdominal pain, constipation, diarrhea and rectal bleeding
  • More severe cases can cause malabsorption, obstructions, free fluid in the abdomen in weight loss
  • Symptoms often sudden onset, sudden resolve – relapsing/remitting
  • Dense eosinophilic infiltration in colon
  • Infiltration can occur in one large contiguous region or smaller isolated regions
  • No true consensus on what constitutes above average eosinophil count in GI tract
  • Sometimes have too many eosinophils in blood
  • Patients often have elevated total IgE
  • Treated with elimination diet, steroids, ketotifen and immunosuppressants

 

 

How to eat low histamine if you’re me

As requested, the details on how I eat low histamine.

The low histamine diet is confusing. There are several lists of which foods are high and which are not. Various sources cite different instructions for food preparation, storage, etc. There isn’t a lot of agreement on what is considered best practice for following a low histamine diet. I figured out what works for me by trial and error and that is what most people need to do. This is what my life looks like on a low histamine diet.

I started the low histamine diet January 1, 2014. I found a bunch of recipes online and spent three hours in Whole Foods trying to find everything. That first month was phenomenally expensive as I needed to get organic and/or low histamine versions of typical pantry products like oils, flours, spices, sugars and so on. The good news is that after that first month, my food bill has been much more manageable (though still more expensive than competing supermarkets like Stop and Shop).

I chose to follow the low histamine/low tyramine diet you can find on the Canadian Mastocytosis Society page. Foods that are canned or preserved are generally considered not to be low histamine as preservatives can be triggered and something bad is supposedly generating by the canning process (I’m unclear on what that is, but it seems possible to me). Vinegar is not allowed and I used many types of vinegar regularly, so that was a bummer. No wine or liquor for cooking because no fermented products and no alcohol. Several of the prepared sauces I used to cook Thai and Vietnamese food also contained verboten ingredients. When you start this diet, I strongly urge you to look at the labels of everything in your kitchen and discard anything that doesn’t qualify. Most sources recommend doing the diet for thirty days to determine efficacy and using one unapproved ingredient in that time period can really make it hard to tell if it’s helping.

Another big no-no is leftovers, but again there isn’t a real consensus. Not being able to cook meals for an entire week really threw a wrench into my schedule. I used to cook two meals on Sunday and eat the leftovers all week. As a microbiologist, I can verify that bacterial degradation of meat begins quite soon after it’s done cooking and this generates histamine as a side product. So no meat leftovers seemed like a good idea to me. I had to trial other types of leftovers to see what I tolerated.

I eventually got to a decent place with this diet where I was spending more time preparing than before but not a ridiculous amount. This is what that looks like.

I juice a lot. I started juicing this past winter. I am not particularly sensitive to taste so I just chop up a bunch of stuff ahead of time and throw it in. I juice one large mason jar of chopped veggies and one small mason jar of chopped fruit in the morning on weekdays. This gives me about a full 8 oz glass. I chop all the veggies at once and set up the mason jars in the fridge for the whole week. It takes about 45 minutes. Vegetables include carrots, parsnips, celery, celeriac, fennel, parsley, kale, arugula, cucumbers and beets. Beets give me energy, and this is apparently a well known phenomenon. I use ¼ beet per juice because more than that gives me cramps. Fruits include apples, pears, mango, star fruit, passion fruit, pomegranate, longan fruit, lychee, rambutan, and kiwis. I sometimes add ginger. I’m not very sensitive to taste, but if it tastes really bad, I just add a little pomegranate juice and it covers it. So that’s usually what I do for breakfast.

Other breakfasts include apples or pears with honey and peanut butter, scrambled eggs, hash browns or home fries (potato or sweet potato) with onion and black pepper, and Applegate chicken and apple or chicken and maple breakfast sausages.

If I forget to pack a lunch and have to go to work, I eat one of the following: apples and peanut butter, mozzarella with yeast free crackers, or multiple pieces of fruit. I can get these items at a nearby supermarket and they are safe fall backs for me.

If I have some time to prepare food, I usually bring with me one of the following: mashed potatoes with salt and butter, sweet potato casserole, saffron rice, mixed cooked vegetables, various versions of daal (lentil dishes, I usually also add chickpeas) and sometimes yeast free flat bread. I can prepare any of these meals and eat them for the following two days without a problem (so if I cook on Sunday, I can eat it Sunday, Monday and Tuesday). This is really helpful. I store them in mason jars and stick them in the fridge. Some people find it is better for them to freeze anything they don’t eat immediately and then thaw and eat it when they choose. I don’t do well with that.

For dinner, I generally have mashed potatoes and an Applegate chicken and apple sausage. I peel and dice two medium, yellow organic potatoes and add to small pot of boiling water. I then put the sausage in its own small pot of boiling water and both are done in about ten minutes. Quick and easy. Sometimes I use a little turnip instead of the second potato and whip it with butter and sage.

If I’m feeling more adventurous or have more time, I have some other dinner dishes. Saffron chicken and rice is really good. I buy organic meat and eat it the day I bought it. Any meat not eaten is either given to someone who can eat it or thrown away. This also includes anything cooked directly with meat, like the rice in the saffron chicken and rice.

Squash risotto is good. Squash lasagna is good. I eat a lot of squash. I make decent squash soups. There are many different types of squash so if you can eat squash, you can often get a lot of variety in taste and texture with squash. Sometimes I candy squash and beets and walnuts with brown sugar, salt and maple syrup. I can eat the risotto and lasagna for two days after cooking and I can successfully freeze and thaw the squash soup.

I strongly recommend making your own stock, both because it is much cheaper and also because it is much safer for mast cell patients who react to lots of foods. I boil down entire bones. I get bones from an organic food store or keep the bones from something I have cooked (like turkey or chicken). I soak the bones in cold water with the juice of one lemon for a few hours. While I’m doing that, I cook celery, carrots, onions and garlic in butter in a large pot. I add the bones and cold water to that pot. I add quartered onions, turnips and potatoes and whatever miscellaneous veggie odds and ends I have. I season it and add water until it’s about an inch from the top, then turn the heat down really low. Every couple of hours, I remove the debris that has floated to the top and stir the pot. I add more water as needed. I cook it for about twenty four hours, then pour it (with funnel) into mason jars and freeze immediately. This stock is really soothing on my GI tract when it has that burny type of pain.

For snacks, I usually eat peanut butter or potato chips. Plain potato chips are generally safe for me. I will sometimes indulge in chocolate or ice cream if I’m not pushing my luck already that day. I can eat most versions of Rice Krispies treats safely. I can eat cake if I make it (and the frosting) myself. I have some low histamine cookie recipes. I make my own low histamine hummus (I tolerate tahini okay, so sometimes I include it and sometimes I don’t) and will eat that with carrot and cucumber spears.

I really enjoy salads but my GI tract has a hard time with them so I am only recently eating them again. I make salads with lettuce or a green that’s not spinach, cucumbers, lots of chickpeas, black olives (safe for me) and a hummus based salad dressing. It’s pretty good. I pack the salads up in mason jars and the lettuce stays crunchy for a few days.

Eating low histamine can really be a royal pain in the ass because of how much work goes into food prep. However, if you can identify some quick items for when you’re really not feeling well or out of your house, it will seem a lot less stressful. Knowing that I can get a Rice Krispies treat at Starbucks to hold me over until I get home helps a lot. Finding out I can eat some Applegate products which can be prepared in a few minutes has made my life much less stressful. It is really difficult in the beginning because you have to check everything and cook everything from scratch, but once you get in a routine it’s not that bad.

 

 

April 2015: Post summaries and take home points

Chronic urticaria and angioedema: Part 1

  • Urticaria is the medical term for hives.
  • Hives are usually called by allergic processes, but can occur for other reasons.
  • Angioedema is swelling in the dermis, subcutaneous tissue, mucosa and submucosa. It is sort of “inside hives”.
  • Angioedema can be dangerous, especially if it affects the airway.
  • Urticaria and angioedema are closely related.
  • If acute, they last for less than six weeks. If chronic, they last for more than six weeks.
  • Acute urticaria is usually due to activation of mast cells and basophils.
  • Antihistamines and brief courses of steroids usually manage acute urticaria.
  • Chronic urticaria usually does not have an identifiable cause.
  • CU patients can have urticaria and angioedema, either alone or together.
  • Cutaneous mast cells drive CU and histamine is the most important mediator.
  • CU is rarely IgE mediated.
  • CU is associated with several chronic conditions, including autoimmune diseases, neoplastic diseases and thyroid disease.
  • 30-50% CU patients make IgG antibodies to the IgE receptor.
  • 5-10% CU patients make IgG antibodies to the IgE molecule.

 

Chronic urticaria and angioedema: Part 2

  • CU lesions are swollen pink or red wheals of variable size, sometimes with surrounding redness.
  • CU lesions are itchy rather than painful or burning.
  • Angioedema is not itchy, is non-pitting and without redness.
  • Physical urticarias are triggered by environmental sources. There are many types.

 

Prostaglandin E2, mast cells and asthma

  • Prostaglandin E2 has inflammatory and anti-inflammatory effects in the body.
  • PGE2 induces fevers and has many other functions.
  • PGE2 can cause mediator release from mast cells.
  • PGE2 can enhance IgE production by B cells.
  • PGE2 relaxes the smooth muscle and opens the airway.
  • When asthmatics take NSAIDs, their asthma often worsens due to interfering with production of PGE2.

 

Mast cell mediators: PGD2

  • Prostaglandin D2 is the dominant prostaglandin made by mast cells.
  • It has many functions, including regulation of sleep and perception of pain.
  • 9a,11b-PGF2a is a breakdown product of PGD2. Both can be tested for in urine as markers of mast cell disease.
  • PGD2 is a strong bronchoconstrictor and is important in asthma.
  • PGD2 is involved in nerve pain via the COX-1 pathway.
  • Aspirin is commonly used in mast cell patients to inhibit production of PGD2. This protects against PGD2 from both COX-1 and COX-2 pathways.
  • PGD2 causes characteristic mast cell flushing.

 

Prostaglandins and leukotrienes

  • Prostaglandins, thromboxanes and leukotrienes are all types of eicosanoids.
  • Eicosanoids are made from arachidonic acid.
  • COX-1 and COX-2 are enzymes that make prostaglandins.
  • 5-LO (lipoxygenase) makes leukotrienes.
  • Non steroidal anti-inflammatories interfere with COX-1 and/or COX-2, depending on the medication. This interferes with production of prostaglandins.
  • Zileuton is a lipoxygenase inhibitor and interferes with production of leukotrienes.

 

Mast cell medications: Everything but antihistamines

  • Mast cell stabilizers interfere with structures on the cell membrane that prevent with release of mediators.
  • Beta-2 adrenergic agonists relax smooth muscles and open airways.
  • Leukotriene receptor antiagonists interfere with function of leukotrienes.
  • 5-lipoxygenase inhibitors prevent production of leukotrienes.
  • Corticosteroids interfere with activity of mast cells and production of mediators.
  • Proton pump inhibitors reduce gastric acid.

 

Mast cell medications: Antihistamines by receptor activity

  • H1 antihistamines turn off the H1 receptor. This helps with many symptoms.
  • H2 antihistamines interfere with action of the H2 receptor. This helps mostly with GI symptoms, but also skin symptoms.
  • H3 antihistamines modulate nerve pain and may normalize levels of neurotransmitters like serotonin.
  • While three medications are known to have H3 activity, they are not designed for this purpose and have serious risks.
  • Thioperamide is promising as an H3 and H4 blocker, but is not yet available for patient use.

 

Mast cells in nerve pain

  • Mast cells are heavily involved in the generation and sensation of pain.
  • Chronic pain has been associated with mast cell degranulation.
  • Hyperalgesia, exaggerated pain response, is associated with mast cells.
  • Histamine may be important in hyperalgesia.
  • Mast cells can transmit nerve pain signals.
  • Overly sensitive and painful skin can also be caused by mast cells.

 

What do all these words mean? (Part 1)

  • A neoplasm is an abnormal group of cells.
  • SM is a neoplasm.
  • Receptors are proteins on the outside of cells that bind specific molecules. This causes a specific action to occur.

 

What do all these words mean? (Part 2)

  • CD117 (CKIT) is a normal marker found on the outside of mast cells.
  • CD117 is sometimes not seen on the outside of mast cells in biopsies because the test is not very sensitive.
  • Being CD117 positive in a biopsy is not the same as being CKIT positive.
  • Being CKIT positive affects options for chemotherapy and disease classification.
  • CD25 and CD2 are abnormal markers on the outside of mast cells linked to SM.
  • CD30 is sometimes positive on mast cells in SM.
  • CD34 is a marker of cells that become mast cells, and on new mast cells.

 

 

Mast cells in vascular disease: Part 1

  • Mast cells cause formation, progression and destabilization of atherosclerotic lesions.
  • Mast cell released histamine can cause coronary spasms.
  • Histamine can cause acute coronary vasoplasm that results in heart attack. This is called Kounis Syndrome.

 

Mast cells in vascular disease: Part 2

  • Chymase is a mast cell mediator that participates in blood pressure regulation.
  • Chymase release can make atherosclerotic plaques unstable.
  • Mast cell activation increases size of atherosclerotic plaques.
  • Atherosclerosis is not known to be elevated in mastocytosis.
  • Cardiovascular symptoms are common in mastocytosis.
  • Some mastocytosis patients have vascular instability.

 

Effects of Platelet Activating Factor (PAF) in asthma and anaphylaxis

  • PAF is released by many cells.
  • PAF receptors are on many cells.
  • PAF causes airway constriction and is heavily linked to asthma.
  • PAF induces leukotriene production.
  • PAF is correlated to severity of anaphylaxis.
  • PAF causes mast cell degranulation and increased release of PGD2.

 

Anti-inflammatory properties of H1 antihistamines

  • Some H1 antihistamines have anti-inflammatory properties.
  • They reduce eosinophil accumulation near allergic sites.
  • Some H1 antihistamines inhibit bradykinin induced formation of hives.
  • H1 antihistamines have also inhibited allergy processes of methacholine and platelet activating factor.

 

Pharmacology of H1 antihistamines

  • When histamine binds to the H1 receptor, it keeps the receptor “turned on”, causing symptoms.
  • H1 antihistamines prevent histamine from “turning on” the H1 receptor.
  • First generation H1 antihistamines cross the blood-brain barrier, which can interfere with sleep-wake cycle, memory, cardiovascular regulation and cause other effects.
  • First generation H1 antihistamines also bind to other types of receptors.
  • Second generation H1 antihistamines only bind to the H1 receptor.
  • Second generation H1 antihistamines do not cause sedation or the neurologic issues seen in first generation H1 antihistamines.

 

Circadian rhythm of mast cells

  • The circadian clock is the “body’s clock”. It tells the body what to do on a 24 hour cycle.
  • Mast cells and eosinophils have internal clocks.
  • Allergic symptoms, including pulmonary ones, are worse between midnight and morning, with onset around 10pm.
  • This causes sleep disruption, morning attacks”, poor rest and decreased quality of life.
  • Circadian rhythm affects mast cell mediator release.
  • Tryptase and histamine are lower in the afternoon and higher at night.
  • A signal from adrenal glands “starts the clock”.

 

Mast cell inhibitory effects of some microorganisms

  • Some organisms decrease mast cell mediator release.
  • Some of these organisms can cause disease and some are harmless.
  • Lactobacillus and Bifidobacteria are healthy bacteria that inhibit mast cell degranulation and activation.

 

 

 

March 2015: Post summaries and take home points

Allergic effector unit: The interactions between mast cells and eosinophils

  • Eosinophils are white blood cells that have granules like mast cells.
  • Mast cells and eosinophils are often found together in late and chronic stages of allergic inflammation.
  • Mast cells, eosinophils and their effects on the body are collectively called “the allergic effector unit”.
  • Mast cells release signals that affect eosinophil behavior and receive signals from eosinophils. The reverse is also true.
  • Mast cells and eosinophils can activate each other and cause mediator release.
  • Eosinophils make mast cells more responsive to IgE.
  • When mast cells and eosinophils are in contact, eosinophils live longer than usual.

 

Mast cell mediators: Sphingosine-1-phosphate

  • S1P is involved in development of vessels, vascular permeability and immune function.
  • Receptors for S1P are found on many cell types, including mast cells.
  • When the IgE receptor on mast cells is stimulated, S1P is produced and secreted.
  • Histamine can stimulate S1P production.
  • S1P regulates blood pressure and heart rate.
  • S1P is involved in anaphylaxis recovery and probably helps to counteract low blood pressure.

 

Allergic to infections: Other behaviors of toll like receptors

  • Toll like receptors (TLRs) are receptors that bind products from bacteria, fungi and viruses to fight infection.
  • TLRs are found on mast cells.
  • When TLRs are bound, mast cells secrete inflammatory molecules like TNF, IL-6, IL-13 and IL-1b.
  • TLRs function independently of IgE.

 

Leptin: the obesity hormone released by mast cells

  • Leptin is a hormone mostly released by adipose tissue, but also by mast cells.
  • Leptin is a “starvation” signal sent to the brain.
  • Patients with obesity have higher circulatory leptin than those without obesity.
  • Patients with obesity are more resistant to the effects of leptin, so they often feel hungry even if they have eaten.
  • Leptin actives inflammatory cells and induces production of TNF, IL-2 and IL-6.
  • Leptin suppresses signals from the IgE receptor to make mediators.
  • High levels of leptin may suppress ghrelin, the “hunger” hormone.

 

Allergic to infections: How bacteria, viruses and fungi activate mast cells

  • TLRs are found on several cell types, including mast cells.
  • Unlike many receptors that only have one “matching” molecule, TLRs bind lots of molecules.
  • These molecules are usually from infecting organisms.
  • Some molecules induce production of cytokines.
  • Some molecules, like peptidoglycan from bacterial cell walls, may induce degranulation.
  • Viral, fungal and bacterial infections can all cause mast cell activation.

 

Diabetes, steroids and hypoglycemia

  • High levels of glucocorticoids deplete mast cell populations.
  • Glucocorticoids interfere with production and release of stem cell factor, a mast cell growth factor.
  • Glucocorticoids decrease mast cell growth and activity.
  • The mechanism by which this occurs is thought to involve insulin.
  • Insulin activates mast cell signaling pathways.
  • Activity in the HPA axis, which regulates steroid levels, is increased in type I and II diabetes, causing elevated cortisol.
  • Hypoglycemia can cause mast cell degranulation.
  • Anaphylaxis can cause hypoglycemia.

 

Diabetes, mast cells and allergic disease

  • Type I and II diabetes can protect against anaphylaxis and allergic reactions.
  • Mast cells are involved in development of glucose intolerance and insulin resistance.
  • In mice with type II diabetes, mast cell stabilizers protects against glucose intolerance and insulin resistance.
  • In a patient with type II diabetes, treatment with cromolyn normalized plasma glucose and A1C.
  • Type I diabetes has a more complicated relationship with mast cells.
  • Diabetes reduces mast cell degranulation.

 

Questions on bone involvement

  • Osteosclerosis is hardening of the bones.
  • Osteoblast is the cell type that makes new bone.
  • In osteosclerosis, osteoblasts may lay down new bone faster than osteoclasts can eat up old bone.
  • Osteolysis occurs when abnormal cells grow rapidly and inhibit osteoblasts, and osteoclasts do not work fast enough.
  • It is not clear if having osteosclerosis makes progression of SM more likely.
  • People with all forms of SM have been found ot have osteosclerosis.
  • Osteosclerosis with swelling of liver and spleen, presence of CKIT mutation in multiple cell types and high increase of baseline serum tryptase warrants careful monitoring.
  • For mast cell disease, large osteolytic lesions are the “worst” bone involvement because it immediately classifies you as ASM.
  • Multiple bone breaks due to severe osteoporosis also classifies you as ASM.

 

Bone involvement in ISM, SSM, SM-AHNMD and ASM: More literature review (part 3)

  • Osteoporosis is the most common form of bone involvement in SM.
  • Osteoporosis is more common in mast cell patients than in the general population.
  • Patients with rapidly increasing serum tryptase and those without have similar incidence of osteoporosis.
  • Patients with rapidly increasing serum tryptase were more likely to develop osteosclerosis during the period of the study.

 

Bone involvement in ISM, SSM, SM-AHNMD and ASM: Literature review (part 2)

  • Overall, about half of SM patients have bone involvement.
  • Markers associated with both bone resorption and bone formation were higher in mastocytosis patients.
  • Osteoprotegerin is higher in mastocytosis patients. This protein regulates the activity of osteoclasts.
  • Levels of c-telopeptide were significantly higher in patients with SM-AHNMD and ASM than in ISM or CM.
  • Presence of skin lesions does not change risk for osteoporosis.
  • Bone mineral density and serum tryptase do not correlate with serum markers of bone turnover.

 

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

  • In osteosclerosis, your body makes new bone faster than it resorbs it.
  • In osteoporosis, your body resorbs bone faster than new bone is made.
  • In osteolysis, your body resorbs bone faster than new bone is made, but much worse than in osteoporosis.
  • Both osteoporosis and osteolysis can cause pathological fractures.
  • Osteoporosis does not classify you as having ASM.
  • Osteoporosis that caused multiple fractures classifies you as having ASM.

 

 

 

February 2015: Post summaries and take home points

How to activate mast cells: Complement protein C3a

  • The complement system is part of the immune system. It allows infecting organisms to be more readily found and destroyed by the immune system.
  • Mast cells express a receptor for C3a, a fragment produced during activation of the immune system.
  • C3a is an anaphylatoxin. It participates in exaggerating the anaphylactic response.
  • C3a increases vascular permeability, causes smooth muscle contraction, and draws white blood cells to inflamed spaces.
  • In mucosal mast cells (GI mucosa), C3a inhibits histamine and TNF release.
  • In serosal mast cells (skin, peritoneum, respiratory tract), C3a induces degranulation when stimulated by IgE or IgG.
  • Inhaled allergens activate complement system in mucosa of respiratory tract, resulting in formation of C3a.
  • Tryptase can change C3 to C3a.

 

Corticotropin releasing hormone, cortisol and mast cells

  • The term HPA axis refers to the mechanisms by which the hypothalamus, pituitary gland and adrenal glands control each other.
  • The HPA axis regulates many things, including the stress response, immune modulation, emotions, sexuality and digestion.
  • The hypothalamus is in the brain. It turns signals from the nervous system into endocrine signals that allow changes by using hormones.
  • The hypothalamus makes corticotropin releasing hormone (CRH).
  • The pituitary gland makes and releases many hormones, including adrenocorticotropic hormone (ACTH), thyroid stimulating hormone, growth hormone and others.
  • When the pituitary gland receives signals from the hypothalamus, it releases these hormones.
  • CRH from the hypothalamus stimulates the pituitary to produce ACTH.
  • The adrenal glands make and release cortisol, epinephrine, norepinephrine and other molecules in response to hormones from the pituitary.
  • ACTH from the pituitary stimulates the adrenals to produce cortisol.
  • Cortisol tells the hypothalamus to stop releasing CRH and the pituitary to stop making ACTH.
  • Taking steroids regularly suppresses ACTH so your body stops making its own steroids. This is weaning steroids is important.
  • CRH is released in response to stress, such as anaphylaxis.
  • CRH can bind to mast cells and cause release of VEGF.
  • CRH is also released by mast cells.