The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 80

93. How is adrenal insufficiency related to mast cell disease?

Adrenal insufficiency is when the adrenal glands do not make enough cortisol, a stress hormone your body needs to help your body respond to the things happening inside and around it. Not having enough cortisol is dangerous and can be fatal.

Adrenal insufficiency is not the same as adrenal fatigue. Patients with adrenal insufficiency demonstrate lower than normal levels of cortisol. Adrenal fatigue is a term that is used to describe a similar constellation of symptoms as seen in adrenal insufficiency but without the lower than normal serum cortisol level when tested. Adrenal fatigue is not well accepted in main stream medicine.

There are several steps involved in making cortisol. These steps use hormones to tell the body to make other hormones until cortisol is finally made. The molecules that are involved in getting the body to make cortisol are collectively called the HPA axis.

Mast cells interact with the HPA axis a lot and in several ways. I have written extensively about this before.

The activity of the HPA axis can either activate mast cells or stabilize them. It can tell the body to make epinephrine, which decreases mast cell activation. But it can also tell mast cells to make inflammation.

It also works in the other direction. Mast cell activation can activate the HPA axis or not, but it usually activates it. If mast cells generate enough inflammation, that can turn on the HPA axis, which in turn activates mast cells even more. This basically means that if you have frequent mast cell activation, your body can end up in a constant fight or flight response. The inflammation generated can be enormous.

When the body has been in a stress response for too long, the adrenal glands can stop making cortisol, causing adrenal insufficiency. This can cause mast cell activation.

Steroids like prednisone mimic the action of cortisol, the stress hormone. Steroids are sometimes used to treat mast cell disease. The purpose of the steroids is to make cells like mast cells stop causing inflammation. If you take systemic steroids like prednisone routinely, your body can become confused and stop making cortisol on its own. This means that when you stop taking the prescription, your body will not have enough cortisol, causing adrenal insufficiency. This activates mast cells in a huge way. Patients often have a hard time getting back to a good baseline without steroids if they have been on steroids for a while.

There is an autoimmune disease called Addison’s Disease that causes adrenal insufficiency. MCAS sometimes occurs secondary to Addison’s.

 

For further reading, please visit the following posts:

The effects of cortisol on mast cells: Cortisol and HPA axis (Part 1 of 3)
The effects of cortisol on mast cells: Cortisol and HPA axis (Part 2 of 3)
The effects of cortisol on mast cells: Cortisol and HPA axis (Part 3 of 3)
Corticotropin releasing hormone, cortisol and mast cells
Mood disorders and inflammation: High cortisol and low serotonin

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 76

I get asked a lot about how mast cell disease can affect common blood test results. I have broken this question up into several more manageable pieces so I can thoroughly discuss the reasons for this. The next few 107 series posts will cover how mast cell disease can affect red blood cell count; white blood cell count, including the counts of specific types of white blood cells; platelet counts; liver function tests; kidney function tests; electrolytes; clotting tests; and a few miscellaneous tests.

89. How does mast cell disease affect platelet counts?

Before I continue, I want to explain one basic fact. Even though they are often included in the term “blood cells”, platelets are not actually cells. They are actually pieces of an original large cell called a megakaryocyte that lives in the bone marrow. Even though platelets are not really cells, they more or less act like they are.

An unusual thing about platelets is that sometimes a specific trigger can cause platelets to become lower or higher.

There are several ways in which mast cell disease can make platelet counts lower.

  • Swelling of the spleen. This can happen in some forms of systemic mastocytosis, and may also happen in some patients with mast cell activation syndrome, although the reason why it happens in MCAS is not as clear. Swelling of the spleen can damage blood cells and platelets, causing lower platelet counts. If the spleen is very stressed and working much too hard, a condition called hypersplenism, the damage to blood cells and platelets is much more pronounced. This may further lower platelet counts. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Medications. Some medications that are used to manage mast cell disease can cause low red blood cell count. Chemotherapies, including targeted chemotherapies like tyrosine kinase inhibitors, can cause low platelet counts. Non steroidal anti-inflammatory drugs (NSAIDs) are used by some mast cell patients to decrease production of prostaglandins. They can interfere with platelet production in the bone marrow. Proton pump inhibitors, often used by mast cell patients to help with GI symptoms like heart burn, can decrease platelet coun Some H2 antihistamines can also lower platelet production. However, none of these H2 antihistamines are currently used in medicine.
  • Heparin induced thrombocytopenia. Mast cells make and release large amounts of heparin, a powerful blood thinner. When there is an excessive amount of heparin circulating, it can cause your body to incorrectly produce antibodies that cause an immune response to heparin. A side effect of this situation is that platelets are activated incorrectly, which can lead to the formation of blood clots and low platelet counts. Heparin induced thrombocytopenia has only been definitively described in patients who receive medicinal heparin as a blood thinner. However, it is reasonable to assume that this situation can also affect mast cell patients who have higher than normal levels of platelets circulating in the blood.
  • Liver damage. Liver damage is associated with malignant forms of systemic mastocytosis such as aggressive systemic mastocytosis and mast cell leukemia. Liver damage can also occur as the result of IV nutrition, which is sometimes needed by patients with mastocytosis or mast cell activation syndrome. When the liver is damaged enough, it may not make enough of the molecules that tell the bone marrow to make platelets.
  • Excessive production of blood cells. In very aggressive forms of systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia, the bone marrow is making huge amounts of mast cells. As a result, the bone marrow makes fewer platelets and cells of other types.
  • Vitamin and mineral deficiencies. Chronic inflammation can affect the way your body absorbs vitamins and minerals through the GI tract, and the way it uses vitamins and minerals that it does absorb. Deficiency of vitamin B12 or folate can decrease platelet production.
  • Excess fluid in the bloodstream (hypervolemia). In this situation, the body doesn’t actually have too few platelets, it just looks like it. If your body loses a lot of fluid to swelling (third spacing) and that fluid is mostly reabsorbed at once, the extra fluid in the bloodstream can make it look like there are too few platelets if they do a blood test. This can also happen if a patient receives a lot of IV fluids.

There are also reasons why mast cell disease can cause the body to make too many platelets.

  • Anemia of chronic inflammation. This is when chronic inflammation in the body affects the way the body absorbs and uses iron. It can result in iron deficiency. Iron deficiency can increase platelet counts.
  • Hemolytic anemia. In hemolytic anemia, the body destroys red blood cells. This can happen for several reasons that may be present in mast cell patients. Hemolytic anemia can increase platelet counts.
  • Iron deficiency. Iron deficiency for any reason can elevate platelet counts.
  • Excessive bleeding. Mast cell disease can cause excessive bleeding in several ways. Mast cells release lots of heparin, a very potent blood thinner that decreases clotting. This makes it easier for the body to bleed. It is not unusual for mast cell patients to have unusual bruising. Bleeding in the GI tract can also occur. Mast cell disease can cause ulceration, fissures, and hemorrhoids, among other things. Mast cell disease can contribute to dysregulation of the menstrual cycle, causing excessive bleeding in this way. It is not unusual for mast cell patients to have GI bleeding, as well as ulceration, fissures, and hemorrhoids.
  • Sustained GI inflammation. Sustained GI inflammatory disease can cause elevated levels of platelets. Given what we know about mast cell driven GI inflammation, it is reasonable to infer that mast cell GI effects and damage may also elevate platelet levels.
  • Clot formation. If a large clot forms, it can affect the amount of platelets circulating in the blood. Some mast cell patients require central lines for regular use of IV therapies or to preserve IV access in the event of an emergency. Blood clots can form on the outside surface of the line, inside the line, or between the line and the wall of the blood vessel it is in.
  • General inflammation. Platelets are activated by a variety of molecules released when the body is inflamed for any reason. This can translate to increased levels of platelet production.
  • Allergic reactions. Platelets can be directly activated by mast cell degranulation through molecules like platelet activating factor (PAF).
  • Heparin. Heparin can cause platelet levels to increase. As I mentioned above, it can also cause platelet levels to decrease.
  • Removal of the spleen. The spleen can become very stressed and work too hard, a condition called This situation is remedied by removing the spleen. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Glucocorticoids. In particular, prednisone is known to increase platelet counts. Prednisone and other glucocorticoids can be used for several reasons in mast cell patients.
  • Third spacing. If a lot of fluid from the bloodstream becomes trapped in tissues (third spacing), there is less fluid in the bloodstream so it makes it look like there are too many cells. As I mentioned above, this is not really a scenario where you are making too many red blood cells, it just looks like that on a blood test.

For additional reading, please visit the following posts:

Anemia of chronic inflammation

Effect of anemia on mast cells

Mast cell disease and the spleen

MCAS: Anemia and deficiencies

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

MCAS: Blood, bone marrow and clotting

Third spacing

Gastrointestinal manifestations of SM: Part 1

Gastrointestinal manifestations of SM: Part 2

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 72

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 73

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 75

I get asked a lot about how mast cell disease can affect common blood test results. I have broken this question up into several more manageable pieces so I can thoroughly discuss the reasons for this. The next few 107 series posts will cover how mast cell disease can affect red blood cell count; white blood cell count, including the counts of specific types of white blood cells; platelet counts; liver function tests; kidney function tests; electrolytes; clotting tests; and a few miscellaneous tests.

 

88. How does mast cell disease affect white blood cell counts?

Firstly, remember that while mast cells are technically considered white blood cells, they don’t actually live in the blood. That means that except in very severe malignant cases of aggressive systemic mastocytosis and mast cell leukemia, mast cells won’t directly contribute to white blood cell count in a blood test at all. This means that in a regular white blood cell level blood test, none of those cells are mast cells.

There are a couple of ways in which mast cell disease can cause low white blood cell counts. It can also cause low counts of certain types of white blood cells even if it doesn’t cause low white blood cell count overall.

  • Swelling of the spleen. This can happen in some forms of systemic mastocytosis, and may also happen in some patients with mast cell activation syndrome, although the reason why it happens in MCAS is not as clear. Swelling of the spleen can damage blood cells, including white blood cells, causing lower white blood cell counts. If the spleen is very stressed and working much too hard, a condition called hypersplenism, the damage to blood cells is much more pronounced. This may further lower the white blood cell count. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Medications. Some medications for mast cell disease can cause low white blood cell count. These are not common medications, but are sometimes used, especially in patients with long term symptoms that have not responded to other medications, or where organs could potentially be damaged, like in smoldering or aggressive systemic mastocytosis, or severe mast cell activation syndrome. These include medications like cyclosporine and interferon.
  • Chemotherapy. These medications can also decrease white blood cell count. Chemotherapy is used in smoldering systemic mastocytosis, aggressive systemic mastocytosis, and mast cell leukemia. It is sometimes also used in very aggressive presentations of mast cell activation syndrome. Newer chemotherapies are more targeted and can cause fewer side effects. However, all of the chemotherapies used for mast cell disease can cause the side effect of low blood cell counts, including white blood cell count.
  • Myelofibrosis. Myelofibrosis is a myeloproliferative neoplasm that is related to systemic mastocytosis. In myelofibrosis, the bone marrow becomes filled with deposits of scar tissue so that the body cannot make blood cells correctly or in normal numbers. This can decrease white blood cell counts.
  • Excess fluid in the bloodstream (hypervolemia). In this situation, the body doesn’t actually have too few red blood cells, it just looks like it. If your body loses a lot of fluid to swelling (third spacing) and that fluid is mostly reabsorbed at once, the extra fluid in the bloodstream can make it look like there are too few red cells if they do a blood test. This can also happen if a patient receives a lot of IV fluids.

Even if the overall white blood cell count is normal, mast cell patients sometimes have low levels of certain types of white blood cells.

  • Anaphylaxis. Anaphylaxis can cause basophils to be low.
  • Allergic reactions. These can also cause basophils to be low.
  • Chronic urticaria. Chronic hives and rashes can cause basophils to be low.
  • Use of corticosteroids like prednisone elevates certain types of white blood cells while suppressing others. Lymphocytes, monocytes, eosinophils and basophils can also be low from using corticosteroids like prednisone.
  • Prolonged physical stress. Mast cell disease can cause a lot of damage to the body over time, triggering a chronic stress response. This can selectively lower the amount of lymphocytes and the eosinophils in the body.
  • Autoimmune disease. Autoimmune disease often causes one type of white blood cell to be high and another to be low. Many mast cell patients have autoimmune diseases, so while this is not directly caused by mast cell disease, it often occurs in mast cell patients. For example, rheumatoid arthritis can cause low neutrophils.

There are many more ways that mast cell disease can trigger high white blood cell counts, or high amounts of certain types of white blood cells.

  • Inflammation. Any type of chronic inflammation can cause high white blood cell counts and mast cell disease causes a lot of inflammation.
  • Medications. Use of corticosteroids especially can cause high white blood cell counts. Epinephrine and beta-2 agonists like salbutamol/albuterol, used to open the airway, can also cause high white blood cell counts.
  • Autoimmune disease. Many mast cell patients have autoimmune diseases, so while this is not directly caused by mast cell disease, it often occurs in mast cell patients.

There are several instances where mast cell disease can trigger elevated levels of certain subsets of white blood cells.

  • Swelling of the spleen. I mentioned above that spleen swelling can damage blood cells, causing their levels to be low. Paradoxically, sometimes having a swollen spleen can cause lymphocytes to be high. There are several theories about why this may occur but there is no definitive answer currently.
  • GI inflammation. Chronic inflammation in the GI tract can cause the body to overproduce monocytes. Certain types of inflammatory bowel disease, like ulcerative colitis, can cause high basophils.
  • Allergies. Allergic reactions of any kind will elevate both basophils and eosinophils.
  • Mast cell activation of eosinophils. Mast cells activate eosinophils, which activate mast cells. It is a nasty cycle that causes a lot of symptoms and can be very damaging to organs affected. It is not unusual for mast cell patients to have high numbers of circulating eosinophils. It is also not unusual for mast cell patients to have higher than expected numbers of eosinophils in biopsies, especially GI biopsies. Eosinophilic GI disease also has some overlap with mast cell disease so some patients have both.
  • Mast cell activation of basophils. Basophils are closely related to mast cells and also degranulate in response to allergic triggers and during anaphylaxis.
  • Autoimmune disease. Autoimmune disease often causes one type of white blood cell to be high and another to be low. Many mast cell patients have autoimmune diseases, so while this is not directly caused by mast cell disease, it often occurs in mast cell patients. For example, lupus can cause eosinophilia.
  • Anemia. Iron deficiency is common in mast cell disease. Iron deficiency anemia can increase basophil levels.
  • Vascular inflammation. Mast cell activation has been repeatedly linked to inflammation of blood vessels. This can elevate blood monocyte level.
  • Medication. Use of corticosteroids like prednisone directly increase neutrophil levels.
  • Proliferation of myeloid cells. Overproduction of certain types of blood cells by the bone marrow, including mast cells, can elevate basophils.
  • Obesity. Obesity has been linked many times to chronic inflammation. Mast cell disease can directly cause weight gain by causing high levels of the hormone leptin. Obesity may cause high levels of monocytes.
  • Third spacing. If a lot of fluid from the bloodstream becomes trapped in tissues (third spacing), there is less fluid in the bloodstream so it makes it look like there are too many cells. As I mentioned above, this is not really a scenario where you are making too many white blood cells, it just looks like that on a blood test.

For additional reading, please visit the following posts:

Allergic effector unit: The interactions between mast cells and eosinophils

Anemia of chronic inflammation

Effect of anemia on mast cells

Explain the tests: Complete blood cell count (CBC) – White blood cell count

Explain the tests: Complete blood cell count (CBC) – High white blood cell count

Explain the tests: Complete blood cell count (CBC) – Low white blood cell count

Mast cell disease and the spleen

MCAS: Anemia and deficiencies

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 72

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 73

Third spacing

 

Rare disease month, day 1: Adrenal insufficiency (Addison’s disease)

Adrenal insufficiency is a condition defined by inadequate production of glucocorticoids. Other hormones, such as mineralocorticoids and androgens, may also be deficient. Adrenal insufficiency was first characterized by Thomas Addison in 1855. For this reason, adrenal insufficiency is often called Addison’s Disease, particularly the primary form.

Cortisol is the dominant glucocorticoid in humans and performs a wide array of essential functions. It is well known as a driver of stress response and modifies metabolic functions to lessen the impact of stress on the body. Its primary functions include increasing blood sugar, blood pressure, and heart rate; bronchodilation; and dampening immune response and inflammation. Patients with adrenal insufficiency are dependent upon replacement steroids and require them daily.

Common symptoms of adrenal insufficiency include fatigue, weakness, weight loss, low blood pressure (sometimes seen as orthostatic hypotension), anxiety, nausea, vomiting, diarrhea, sweating, and personality changes, among others. Darkening of the skin is often a clinical sign seen in primary adrenal insufficiency.

Adrenal insufficiency is life threatening and can be fatal. Prior to 1949, when synthetic cortisone became available, AI was universally fatal via adrenal crisis (also called Addisonian crisis). Adrenal crisis is the manifestation of critical cortisol deficiency. Symptoms can include fever; seizures; psychosis; severe abdominal, back and leg pain; fainting; vomiting and diarrhea; and dysregulation of electrolytes, including elevated potassium and calcium and low sodium. The only treatment for adrenal crisis is immediate corticosteroid replacement. Patients with adrenal insufficiency are recommended to always carry hydrocortisone for IM injection in the event of an emergency.

Primary adrenal insufficiency affects approximately 4.4-6 people per million. 80-90% of cases in developed countries result from autoimmune adrenalitis/ autoimmune Addison’s disease. This condition is sometimes seen as part of autoimmune polyendocrinopathy syndrome, in which several other endocrines are also impacted. Certain infections, such as histoplasmosis, coccidioiodomycosis, and tuberculosis; adrenoleukodystrophy; adrenal hyperplasia; and use of certain medications can cause primary adrenal insufficiency.

Secondary adrenal insufficiency affects approximately 150-280 people per million. It is most commonly caused by long term use of glucocorticoids which disrupts the HPA axis, the collective term for the hormonal system the body uses to regulate cortisol levels. Other causes for secondary AI include curing Cushing’s Syndrome, tumors of the hypothalamus, pituitary tumors, and trauma to or surgical removal of the pituitary. Complete cessation of glucocorticoids for up to a year is often necessary to trigger endogenous cortisol production but this cannot always be done safely. Many patients with secondary AI require replacement steroids for life.

Cortisol impacts mast cells in several ways, which have been rehashed extensively here and here.

For more information on adrenal insufficiency: http://www.nadf.us

 

Reference:

Charmandari E, et al. (2014) Adrenal insufficiency. The Lancet. (Seminar)

The effects of cortisol on mast cells: Part 3 of 3

In some cases, glucocorticoids can immediately treat issues with immune activation. This immediate action is not well understood.  In animal models, glucocorticoids can stop allergic reactions in five minutes and significantly decrease short term histamine release. Mostly though, glucocorticoids mitigate mast cell activation through delayed actions. This is one of the reasons why premedication with steroids prior to surgery or procedures is recommended to start the day before.

Glucocorticoids affect gene expression, which is one of the reasons they take time to work. Gene expression is very complicated and is highly regulated by cells. Genes are part of your DNA. Think of each gene as a message.  When your cell wants to make something using a gene, like a protein, it makes a copy of the message in the gene and then takes it to another part of the cell to make the protein. There are many molecules that affect how easy it is to make something from a gene.  Some molecules make it easier and others make it harder.  Transcription factors are molecules that sit by genes that make it easier for their message to be made. Interfering with making the message and getting it to the part of the cell where it can make something, like the protein, can drastically alter the behavior of a cell.

One of the major ways that glucocorticoids interfere with making the message is with glucocorticoid receptors. Many people know that receptors are often on the outside of a cell and they are activated when a molecule fits into the receptor like a key into a lock.  Glucocorticoid receptors do not work like that.  They are small molecules inside cells that are changed when glucocorticoids bind to them.

Cortisol, or other glucocorticoids, bind to the glucocorticoid receptors inside mast cells. When this happens, they interfere with the transcription factors so it is really hard to use the genes. Some of these transcription factors are called NF-kB and AP-1.  When glucocorticoid receptors have been activated in the mast cell, the transcription factors can’t help to use the genes.

Cytokines are molecules that cells use to “talk” to each other. Another kind of signal.  Glucocorticoids directly interfere with use of cytokine genes so that they aren’t made.  Mast cells make many cytokines and they are responsible for a lot of late phase allergic symptoms.  Manufacture of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, GM-CSF, TNF and IFN-g (interferon gamma) can all be suppressed with glucocorticoids.

If the cytokine genes have already been used, glucocorticoids can still prevent them from being made. When you use a gene to make something, it creates a messenger RNA (mRNA) that carries the message.  If the mRNA falls apart, nothing will be made from the gene. Glucocorticoids make the messages fall apart before making anything for many cytokines, including IL-1, IL-2, IL-6, IL-8, TNF and GM-CSF.

References:

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.

Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.

Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.

Sinniah A, et al. The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil. International Immunopharmacology 2016: 32, 87-95.

The effects of cortisol on mast cells: Part 2 of 3

Glucocorticoids, like cortisol, can affect mast cells in many ways. As I discussed in my previous post, there are many ways for mast cells to release mediators when activated. In all of these pathways, there are many molecules involved that carry the signal, like people passing the Olympic torch. In mast cells, one of the molecules that suppresses inflammatory activation signal is called SLAP (yes, really).  Cortisol increases the amount of SLAP in mast cells so inflammatory activation signals are suppressed.

An important step in degranulation is changing the amount of calcium inside the cell and moving it to different parts of the cell. In some studies, glucocorticoids can affect this movement of calcium. Other studies have found that in some pathways, glucocorticoids don’t affect calcium movement, but instead interfere with things like the IgE receptor.

Cortisol is also thought to directly inhibit stem cell factor (SCF) binding to the CKIT receptor. When SCF binds to the CKIT receptor, this sends a signal to the mast cell to stay live.  This means that taking glucocorticoids can let mast cells die at the appropriate time. SCF also tells mast cells to go to inflamed spaces.  By blocking this signal, glucocorticoids suppress inflammation.

One of the ways that molecules carry a signal is by changing the next molecule in the pathway. A big way that cells changing molecules is by chopping off a piece of them called a phosphate group.  This is done by special enzymes called phosphatases.  Glucocorticoids affect the availability of phosphatases so they aren’t able to get to the right part of the cell to carry the signal.  When this happens, there is less activation and less histamine release.

Arachidonic acid is the molecule modified to make eicosanoids (leukotrienes, thromboxanes and prostaglandins.) Glucocorticoids directly interfere with the production of these molecules in multiple ways.  The first way is by interfering with COX-2, one of the enzymes that makes prostaglandins.  Another way is by preventing arachidonic acid from being released to a place where they can be turned into leukotrienes, thromboxanes and prostaglandins.  This occurs because glucocorticoids increase the amount of a powerful anti-inflammatory molecule called annexin-I.  Annexin-I inhibits the molecule that releases the arachidonic acid, called phospholipase A2.

Annexin-I was the subject of an important paper earlier this year. In trying to identify exactly how mast cell stabilizers like ketotifen and cromolyn work, the researchers discovered that treatment with mast cell stabilizers decreased degranulation and increased annexin-I made by mast cells.  They also found that glucocorticoids had the same effect.

References:

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.

Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.

Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.

Sinniah A, et al. The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil. International Immunopharmacology 2016: 32, 87-95.

The effects of cortisol on mast cells: Cortisol and HPA axis (Part 1 of 3)

Things I’m not great at: Knowing how many posts I need to cover all the effects cortisol has on mast cells.  So this is the first of three posts on cortisol and mast cells.  Then we will get back to the tables breaking down the effects of hormones on mast cells.
Cortisol is a glucocorticoid steroid hormone with far reaching anti-inflammatory actions. It is the product of a very complex endocrine system called the HPA axis.  HPA stands for hypothalamus-pituitary-adrenal.  The hypothalamus is in the brain and the pituitary is a small structure on the edge of the hypothalamus.  The adrenal glands are above the kidneys.

The hypothalamus, pituitary and adrenal glands all release a number of hormones that affect many bodily functions. Briefly, the hypothalamus receives signals from the nervous system to make corticotropin releasing hormone (CRH).  CRH induces the pituitary to make adrenocorticotropin hormone (ACTH). ACTH induces the adrenal glands to make cortisol.

Cortisol is most well known as the stress hormone, although it has many other functions. It can be released as a response to inflammation or physical or emotional trauma.  In such instances, signals from the nervous system tell the hypothalamus that it needs to make CRH.  CRH triggers vasodilation and increased vascular permeability to allow immune cells move from the bloodstream to inflamed spaces in tissue.  CRH also triggers manufacture of ACTH, which then triggers manufacture of cortisol.

When cortisol levels are high in the adrenal gland, epinephrine can be made from norepinephrine. Cortisol is thought to regulate the enzyme that makes epinephrine at several steps in the process.  Epinephrine is also part of the stress response and participates in the fight-or-flight response.

The role for which glucocorticoids are most often prescribed is suppression of inflammation. Cortisol production is initiated very early in an inflammatory response. Cortisol counteracts vasodilation seen by many inflammatory mediators.  Cortisol also decreases vascular permeability so immune cells are not able to easily leave the bloodstream and move into tissues.  Cortisol also affects gene expression so that inflammatory products are not made as much and anti-inflammatory products are made more.  (This will be discussed in great detail when I cover how cortisol affects mast cells.)

A number of synthetic glucocorticoids, like prednisone and dexamethasone, have similar behaviors and functions. The medication hydrocortisone functions the most like cortisol in the body.  Synthetic glucocorticoids stay in the blood longer and are more bioavailable than cortisol.  The amount of cortisol produced by the body changes throughout the day in time with other functions.  Synthetic glucocorticoids cannot mimic these changes exactly and are thus inferior to cortisol.  Small changes in amount of glucocorticoid can have major effects.

References:

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.

Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.

Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.

Mast cell medications: Everything but antihistamines

The following medications listed are available in oral, intramuscular or intravenous formulation. Not all medications are available in the US or Europe. Topical and inhaled medications are not included in these lists.

Mast cell stabilizers interfere structures on the cell membrane required for degranulation and thus prevent the release of granule contents, including histamine.

Mast cell stabilizers
Cromolyn sodium/ Cromoglicic acid/ Nedocromil
Ketotifen
Omalizumab*
Quercetin
*mechanism unclear

 

Beta-2 adrenergic agonists cause smooth muscles to relax, which allow airways to open. These are used almost exclusively in asthma and pulmonary disease, which a secondary use in controlling uterine contractions in labor.

Beta-2 adrenergic agonists
Albuterol
Terbutaline

 

Leukotriene receptor antagonists work by interfering with the function of leukotrienes by blocking the CysLT1 receptor. Leukotrienes are heavily involved in airway reactivity and inflammation.

Leukotriene receptor antagonists
Montelukast
Pranlukast
Zafirlukast

 

5-lipoxygenase inhibitors prevent leukotrienes from being made.

5-lipoxygenase inhibitor
Curcumin
St. John’s Wort
Zileuton

 

Corticosteroids interfere with the activity of mast cells and production of mast cell mediators.

Mast cell stabilizers
Budesonide*
Dexamethasone
Hydrocortisone
Prednisone
Prednisolone
*taken orally, with effects local to the GI tract

 

Proton pump inhibitors reduce the production of gastric acid and treat heartburn, nausea and reflux. This can also be achieved by H2 antihistamines and for this reason, the two classes are often confused. The following medications, which are taken often by mast cell patients, have no known antihistamine effect. They can safely be taken with H2 antihistamines and help many mast cell patients, but it is important to clarify that they are NOT antihistamines.

Proton pump inhibitors
Dexlansoprazole
Esomeprazole
Ilaprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole

Diabetes, steroids and hypoglycemia

Following alloxan induction of diabetes, rats overexpress glucocorticoids. This in turn depletes the mast cell populations in the skin, lungs and intestines. Glucocorticoids interfere with production and expression of tissue cytokines and stem cell factor, a growth factor for mast cells.

Several experiments have definitively proven that these steroids are responsible for downregulating mast cell growth and activity. Treating diabetic rats with the steroid receptor blocker RU486 or removing adrenal glands on both sides of the animal causes an increase in intestinal mast cell numbers and IgE formation.

The mechanism by which steroids confer these effects is thought to involve insulin. Glucocorticoids inhibit secretion of insulin in the pancreas. In turn, insulin release decreases systemic glucocorticoids. Additionally, insulin also activates mast cell signaling pathways. In the presence of insulin, antigen induced mast cell degranulation and survival is upregulated. In diabetic rats, administration of insulin recruits mast cells and increases response to antigen. Insulin treatment can reverse the reductions in mast cell populations, histamine production and IgE release seen following alloxan administration.

Increased activity of the HPA axis is often seen in type I and II diabetics, resulting in elevated cortisol. One study showed that appropriate activity can be restored with insulin treatment. This is achieved by a complex mechanism in which expression of glucocorticoid receptor mRNA is elevated in the pituitary, facilitating glucocorticoids to suppress expression of ACTH release.

 

Can hypoglycemia cause mast cell degranulation?

Yes. Activation of histamine 1 and 2 receptors as a result of insulin or hypoglycemia causes release of ACTH. Hypoglycemia (low blood sugar, which can also be induced after administration of insulin) normally increases ACTH levels in the blood. However, higher than normal histamine levels in the blood can interfere with the action of ACTH, which would normally address hypoglycemia via production of glucocorticoids. One study found that this effect can be mostly ameliorated by pretreating with antihistamines, though I suspect in mast cell patients, this may not achieve the full response seen in non-mast cell patients.

 

Can anaphylaxis cause hypoglycemia?

Yes. In instances of severe stress (emotional or physical), corticotropin-releasing hormone (CRH), neurotensin and substance P are released. Among other things, CRH can induce mast cell degranulation (of note, CRH does not directly induce histamine release via degranulation). CRH also causes increased expression of the IgE receptor on mast cells, which increases the likelihood of being stimulated and thus degranulation (this may cause histamine release). In tandem, neurotensin and substance P increases the expression of the CRHR-1 receptor for CRH on mast cells so that they are more sensitive to CRH. Likewise, neurotensin and substance P act on mast cells via receptors to induce degranulation (this causes histamine release). As a result of this degranulation, histamine and other mediators are present to inhibit the action of ACTH, which would otherwise increase blood sugar (via the production of cortisol, epinephrine, and norepinephrine).

 

References:

Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.

Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.

Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.

Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673

Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2

Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.

Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.

Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.

Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.

S.C. Cavalher-Machado, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.

Corticotropin releasing hormone, cortisol and mast cells

The term “HPA axis” refers collectively to the signals and feedback loops that regulate the activities of three glands: the hypothalamus, the pituitary gland, and the adrenal glands. The HPA axis is a critical component of the body’s stress response and also participates in digestion, immune modulation, emotions, sexuality and energy metabolism.

The hypothalamus is part of the brain. It performs several integral functions. It regulates metabolism, makes and releases neurohormones, and controls body temperature, hunger, thirst, circadian rhythm, sleep and energy level. It is also known to affect parenting and attachment behaviors. It effectively turns nervous system signals into endocrine signals by acting on the pituitary gland.

The pituitary gland is a small gland at the bottom of the pituitary. The anterior portion of the pituitary is part of the HPA axis. It makes and releases several hormones, including human growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone (ACTH), prolactin, luteinizing hormone and follicle stimulating hormone. All of these hormones are released when hormones released by the hypothalamus act on the pituitary.

The adrenal glands are located on top of the kidneys. They primarily synthesize and release corticosteroids like cortisol and catecholamines like epinephrine and norepinephrine in response to action by the pituitary.   It also produces androgens and aldosterone.

The hypothalamus synthesizes vasopressin and corticotropin releasing hormone (CRH).   Both of those hormones stimulate the release of ACTH by the pituitary gland. ACTH stimulates the adrenals to make glucocorticoids (mostly cortisol). The cortisol then tells the hypothalamus and pituitary to suppress CRH and ACTH production. This is called a negative feedback loop.

Cortisol acts on the adrenals to make epinephrine and norepinephrine. Epi and norepi then tell the pituitary to make more ACTH, which stimulates the production of cortisol.

When you take steroids regularly, it suppresses ACTH so that your body stops making its own steroids. This is why weaning steroids is very important. By weaning, your body should gradually start making its own cortisol to replace the deficit when you lower your steroid dose. However, this doesn’t always work. People who do not make enough cortisol on their own are called adrenally insufficient and are steroid dependent. People with this condition can suffer “Addisonian crises” if their steroid levels drop dangerously low. This is a medical emergency.

CRH is released by the hypothalamus in response to stress. This drives the production of cortisol to help manage stressful situations of either a physical or emotional nature. Mast cell attacks and anaphylaxis are examples of physically stressful situations that stimulate release of CRH.

CRH binds to CRHR-1 and CHRH-2 receptors on various cells, including mast cells. When it binds to mast cells, it stimulates the release of VEGF, but not histamine, tryptase or IL-8. This type of release is called selective release as it does not involve the release of preformed granules (degranulation.) Additionally, CRH is also released by mast cells. This can act on the mast cells or other cells with CRHR receptors, like those in the pituitary. The exact purpose of mast cells releasing CRH is not clear.

 

References:

Theoharis C. Theoharides, et al. Mast cells and inflammation. Biochimica et Biophysica Acta 1822 (2012) 21–33.