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

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)

Privilege

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

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

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

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

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

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

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

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

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

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

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

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

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

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.