Hyperadrenocorticism (Cushing's) For Dummies

Cushing's disease is a rather complex thing involving a couple of different glands, many hormone messengers, and a lot of chemical feedback. Since this is a pretty common disease in dogs, I thought I'd try to put together an easy-to-understand explanation that doesn't include too many 15-letter words.

First, let's imagine a large corporation that makes refrigerators. They have a head office where the big decisions are made, and two factories several hours away that do the manufacturing and distribution. The head office keeps track of demand for fridges based on market research and the number of orders coming in. The factories just respond to orders from the head office.

Head office contacts the factories every day via text message. When demand rises, they text instructions to both factories telling the managers to increase production and make more fridges. If there is no demand, there are no texts sent and the factory managers only make enough fridges that day to keep the machinery running.

One night you drive by Factory A and notice that all the lights are blazing. The parking lot is still full of employees' cars. The machinery is geared up so high you can hear it from the street. Refrigerators are flying off the assembly line so fast that there aren't enough delivery trucks to take them away. The loading docks and yard are starting to fill up with fridges. Obviously the factory is working overtime.

The five days later you drive by again. No trucks have been taking the fridges away, but the factory is still at maximal output. You have to stop because the road is blocked with fridges piled four high. There are fridges everywhere. Annoyed, you get out of the car and think about what has happened.

If you understand this scenario, you have a good understanding of Cushing's disease. In this case, the factories are two small glands just ahead of the kidneys - the adrenal glands. Instead of refrigerators, they are producing a hormone called cortisol.  And instead of a head office, we are dealing with the pituitary gland in the brain ("head" office, get it?).

The pituitary senses low cortisol levels and sends a text message (a hormone called ACTH) to the adrenal glands. The ACTH makes the adrenal glands produce more cortisol. As soon as cortisol levels in the blood rise to normal, the pituitary stops making ACTH and the adrenal glands stop making cortisol. This is a very nice example of a feedback loop, and it keeps the body cortisol levels within a very narrow normal range.

In our factory story, there has obviously been a miscommunication between the head office and the factories. Nobody could ever use this many refrigerators! How could this happen?

Scenario one is that there is an evil madman in the corporate head office, bent on crippling the city and choking the roads with refrigerators. He has been sending texts non-stop to the factory, giving them orders to produce more and more fridges despite the fact that there is obviously no demand. His market surveys tell him that there are plenty of fridges out there to supply the people who want them, but he doesn't care. He's off his rocker. More fridges!

The other possibility is that the factory has lost communication with head office. The aren't getting any instructions by text, but they are still making a ton of fridges. Perhaps the factory manager has finally succumbed to stress, or the workers are revolting. They have locked the doors and are hunkered down, making fridges like there's no tomorrow. The factory has become autonomous.

In Cushing's disease we have a madman somewhere. Either the pituitary has a tumor that is excreting tons of ACTH, which makes the adrenal glands produce tons of cortisol, or one of the adrenal glands has gone mad (has a tumor) and is making cortisol without a request from the pituitary gland.

It's important to know which situation we have, because the treatments are quite different. If we have an adrenal gland gone crazy, we can operate and remove it to solve the problem. The other adrenal gland will take over and produce all the cortisol the body needs. If the pituitary is out of control, we can give a drug that decreases the amount of cortisol produced by the adrenal glands.  Even if the texts are being sent, the factory won't overproduce.

Diagnosis

To make a diagnosis of MegaFactory, we can send some false information to the head office and see if it decreases the factory output at all. We could send out a press release saying that another factory has just made a million refrigerators, and there is no more demand. A smart head office will stop sending text orders to its factories, since it won't be able to sell any fridges that they make. If everything is normal and in control, refrigerator output will drop to zero. If there are crazy people in the head office or the factories, output will remain high.

In medical terms, we do a test called low-dose dexamethasone suppression test (LDDST). We take a blood sample to get baseline cortisol levels. We then give an injection of a drug called dexamethasone, which is not detectable on the test but which is very good at shutting down the pituitary's output of ACTH. A normal dog will have very little ACTH after the injection, and the normal adrenal glands will respond by shutting down production of cortisol. We take blood samples 4 and 8 hours after the injection to measure cortisol levels.  If they are still high, we have hyperadrenocorticism.

Once we've diagnosed hyperadrenocorticism, we can figure out whether it's a factory problem (adrenal gland tumor) or a head office problem (pituitary tumor). One way to do this is to actually look at the factories.

If we have two factories that are both at maximum production, it's because the head office is sending too many text message orders. (We could theoretically have two crazy factory managers, but that is rare to the point of being almost unheard of.) We should be able to see some change in the factories from the outside - it's probably expanded to kick up production.

To look at the adrenal glands we use ultrasound. We can actually see whether they are normal or enlarged. If both are large, the pituitary is the source of the problem. It is sending out ACTH messengers constantly, telling both adrenal glands to produce more cortisol. They have to get larger to meet the demand.

If Factory A is stacking fridges in the street and Factory B has downsized to a skeleton crew and isn't even making fridges any more, then the problem is Factory A.  It is making so many fridges that head office isn't sending any texts to either factory, since there is a glut of refrigerators on the market.

In HAC terms, if one adrenal gland is large and one is small, the large adrenal gland is the problem. It is producing cortisol all on its own. The pituitary is normal, and it knows that there is a lot of cortisol around. It's not sending any ACTH because it doesn't want more cortisol made. The normal adrenal gland hasn't seen any ACTH in a long time. It has laid off workers and shrunken. But the abnormal gland doesn't need ACTH in order to make cortisol, since it is now autonomous. So we end up with one big fat adrenal and one shriveled adrenal.

As you can see, it might take more than one kind of test to determine what form of disease a dog has. Sometimes we can make a diagnosis of the type of HAC after one test. Sometimes it will take 3 different types of test to know for sure. Although this can get costly, it is in the patient's best interest to know which type we are dealing with so that we can start appropriate treatment.