Understanding Cushing's Disease for Dummy’s

Cushing's is a kind of disease where there's just too much cortisol, and why is that? Remember the hypothalamus where we can find our pituitary and the adrenal gland where it is divided into two parts of which are the medulla and then the outer part is the cortex. There's different types of molecules or hormones that are actually produced that are really important that the hypothalamus makes, it is a very specific molecule called CRH which is referred to as Corticotropin Releasing Hormone. So, when the hypothalamus makes CRH, CRH comes down and stimulates the anterior pituitary and makes a molecule called ACTH also called Adrenocorticotropic Hormone.

So, the hypothalamus makes CRH tells the anterior pituitary to make ACTH the ACTH then comes down the receptors on the Adrenal Cortex. The adrenal has three parts, the Zona glomerulosa the Zona fasciculata and then the Zona reticularis.

The Zona fasciculata is responsible for making a very specific molecule that is pushed into the blood called cortisol. Patients who have Cushing's syndrome has their adrenal gland as the problem and they're just producing too much cortisol, maybe due to a tumor there maybe there's some hyperplasia in the adrenal gland or whatever it may be that’s causing a problem, where the adrenal gland is the source of high cortisol.

In Cushing's disease where there is too much production of ACTH because of the anti-pituitary or there's somewhere else in the body that's making too much ACTH that's stimulating hyper stimulating to the adrenal cortex and making more cortisol.

CLINICAL MANIFESTATIONS OF CHUSHING DISEASE

1. HOW IT AFFECTS THE SYMPATHETIC NERVOUS SYSTEM

The autonomic nervous system usually in the lateral parts (the lateral ganglion and the lateral gray horns) these generally have a lot of ability to innervate a lot of viscera so the autonomic nervous system particularly the sympathetic nervous system increases the activity or the sensitivity where it releases norepinephrine. Norepinephrine loves to bind onto these adrenergic receptors on the heart very powerfully.

In the heart there are receptors called beta 1 adrenergic receptors which are located on the actual contractile portion of the heart in the SA node, AV node, the bundle of hiss, and the bundle branches. This beta 1 adrenergic receptors are very special to know because when norepinephrine binds onto this beta 1 adrenergic receptors it does two particular things:

a. When the beta 1 adrenergic receptors is stimulated it increases the heart rate. It is like a fire action potential that quickly rashes through the AV node all through the bundle of hiss and the bundle branches. If it binds to the contractile portion it will also increase the stroke volume and cardiac output leading to an increase of blood pressure.

b. Stimulation of the Alpha 1 adrenergic receptors are present on the blood vessels and arteries and when norepinephrine binds onto these receptors, it squeezes the life out of them and increases the vasoconstrictive response which helps to increase the blood pressure.

Cortisol normally increases the sensitivity and the activity of the sympathetic nervous system and it increases the up-regulation of the beta 1 receptors and alpha-1 receptors. As norepinephrine binds to these it produces a response, when there is a high level of cortisol it amplifies response of balance between the sympathetic nervous system and the cardiovascular system is it increases the activity and the sensitivity of the sympathetic nervous system.

By increasing the number of beta 1 and alpha-1 adrenergic receptors and increasing the response whenever norepinephrine binds onto them it has an amplified response and get this particular effect on the blood pressure by increasing it. it's very interesting because as the blood pressure increases it can produce something called secondary hypertension. So basically, patients have very high blood pressure and their blood pressure doesn't typically respond to one, two, and sometimes three anti-hypertensives that's really important to remember in the clinical vignette is a patient coming with high blood pressure still having high blood pressure despite multiple anti-hypertensives.

2. HOW IT AFFECTS THE IMMUNE SYSTEM

Neutrophils are supposed to do something called margination, so let's say for example there's a pathogen and neutrophils slides along the vessel wall and then they squeeze through the vessel through what's called diapedesis. Neutrophils roll along the blood vessel edges and then they squeeze through the blood vessel so that they can get out here and fight off these bacteria destroy it, but because there is a high level of cortisol it suppresses the margination response and neutrophils can't stick to the blood vessel wall to squeeze through to fight off the bacteria.

The inhibition of neutrophil margination produces two things one is it can actually make white blood cell count higher but it inhibits the body from being able to fight off infections. Another, it suppresses the T Cell response. T cell proliferation are important because they help to be able to allow for the body to generate proper immune responses. Because of the increase level of cortisol, the body is unable to generate proper immune response plasma cells which are supposed to produce antibodies to fight off these bacteria. With the inhibition of neutrophil margination and T cell proliferation the patient is at high risk for infection.

In general, they're very high risk for infection because they have an immunosuppressive effect that's why have you ever noticed whenever you're really stressed in life, sometimes high stressor situations can result you to getting really sick this? This is one of the reasons, the cortisol production is kind of a long-term stress response whenever you get really acutely stressed your sympathetic nervous system becomes activated but that long-term stress response that continues on for your daily life struggles is the cortisol response and so that's why patients who are highly stressed have hypertension and they can also high risk for infections.

3. HOW IT AFFECTS THE METABOLIC AND ENDOCRINE SYSTEM

A high levels of cortisol acts on the liver and provokes two particular processes in the liver and one is it does something called gluconeogenesis. Gluconeogenesis is basically where things that are non-carbohydrate sources such as amino acids are converted into glucose. The second one is called glycogenolysis where the liver breaks down glycogen into glucose. So, if the whole point of both of these is that it pushes glucose out of the liver cells into the blood allowing the glucose to shoot through the roof letting the body go through hyperglycemia. Hyperglycemia naturally stimulates the pancreas to produce insulin, but the problem now is cortisol actually may suppress the insulin production as well so cortisol might even have the ability to have a kind of suppression of insulin production so now the glucose levels will continue to be high and this problem with the high glucose levels is this increases the risk for diabetes mellitus.

The two processes the glycogenolysis and the gluconeogenesis will precipitate high glucose levels, which should naturally stimulate the pancreas to produce insulin to shunt the glucose out of the blood and into cells but cortisol may also suppress insulin production to some degree so now the liver continues to have high glucose levels and then end up with an increased risk of diabetes called the diabetogenic effect of cortisol.

Diabetogenic effect has another very profound effect you would think it's a good thing but it's actually kind of a bad thing, whenever there's super high levels of cortisol are it'll bind to the adipose tissue. Remember cortisol is a steroid hormone so it doesn't have extracellular receptors it has intracellular receptors, but because of the increase level of High cortisol it will bind onto these receptors and it'll trigger a process called lipolysis. Lipolysis basically break triglycerides down into free fatty acids and glycerol but here is the problem not only does it simulate a lipolysis it stimulates fat redistribution and this is where it becomes a problem pathologically because it break down fats from the periphery and distribute them to the central part of the body leading to the face getting swollen (moon face), the abdomen gets all puffy (abdominal obesity), and the patients end up with a buffalo hump in the back of the neck.

To be able to have as much glucose as possible fats are broken down to turn into glucose that's called gluconeogenesis same thing proteins and muscles and connective tissue and Bone tissue are utilize for making glucose via gluconeogenesis. So, whenever a person has high levels of cortisol it's going to also bind on to multiple different types of cells so let's say that this is of muscle tissue let's say that this is of connective tissue let's say that this is of bone tissue. High level of cortisol inhibits the synthesis of a very specific type of protein called collagen synthesis. Proteins in the muscles, connective tissues, and bones are broken down to inhibit collagen synthesis which is important especially in connective tissue and Bone. This will lead to atrophy the most commonly affects the proximal muscles so the shoulders and the hips and even in general the extremities would get really small and tiny leading to osteoporosis and fractures and you can also cause atrophy and muscle weakness of the proximal muscles.

Collagen is very heavy in our dermis and supposed to provide a good tensile strength to our skin, and it helps to thicken kind of appearance, helps with kind of the general integrity of our skin but now you start decreasing the collagen that's present in the skin leading to a thing skin. A thin skin loses the Integrity of the skin and that could lead to two particular things called striae and ecchymosis. Ecchymosis is actually a really bad thing where the skin can have a lot a bruising type of appearance and then also because the skin is so thin and don't have a lot of the collagen to repair it cause wound healing to be slow.

MEDICAL AND SURGICAL MANAGEMENT

1. If the patients have a pituitary tumor a transfer nodal resection can be done that'd be the first thing.

2. If the patient have an adrenal tumor cortisol production needs to be suppressed first and let the patient have Ketoconazole. But ultimately, adrenalectomy can be done.

3. If a patient who has some type of like ectopic production a chemo radiation or surgical resection can be done but in the interim until Ketoconazole suppresses the cortisol production.

4. Lastly, if the patient is taking chronic steroids - taper their steroid dose down.