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Question and Answer Period from Cushing’s Patient Education Day, February 2010

Question: Is Cushing’s hereditary?

Dr. Lacroix – For adrenal causes of Cushing’s syndrome, there are some genetic forms. One is with micronodular adrenal dysplasia, sometimes with other tumors, called Carney Complex, where familial cases and responsible genes are now known. This is also true with ACTH-independent bilateral macronodular adrenal hyperplasia as there are now more than 12-15 families which have been described.

For the most common pituitary cause, Cushing’s disease, there are only very few and very, very limited cases of Cushing’s disease reported in the same family. A group in Belgium has recently identified one gene that sometimes can be abnormal in families with pituitary tumors. This is mostly true with prolactin secreting tumors where there are reports of these tumors in families. There are very rare reports of Cushing’s Disease in the same family. For example, I happen to have two patients with Cushing’s who are sisters. I would think that other endocrinologists have seen maybe one or two cases in a single family, but this is very rare.

Dr. Weiss: There is an interesting paper that was recently published based on detailed genealogy studies in Utah. Pituitary tumors of all types were found to have increased incidence in the second generation, not the first generation. The genes involved have not been identified as this data is only from genealogy studies.

Dr. Katznelson: A familial syndrome such as MEN 1, (multiple endocrine neoplasia, type 1) is a syndrome of the 3 P’s; pituitary tumors, which can include Cushing’s, parathyroid and pancreas. So this is a case where family members can have different types of tumors. The most common tumor is a parathyroid tumor, which causes high calcium levels which can lead to kidney stones. Thus families with this particular mutation have an increased incidence of kidney stones.

Question: Is our DNA involved in Cushing’s?

Dr. Vance: There have been studies in all types of pituitary tumors and we have more information in certain types of tumors. There is a change in the DNA and it’s thought that two changes are needed to cause a tumor. There are different mutations, but I don’t think we know the answer as to whether each person has the same mutation that causes a tumor.

Dr. Katznelson: With Cushing’s Disease, we do know that these tumors arise from one cell that started to divide, so something happened in that first cell. What we don’t always know, is what those specific mutations are. Multiple researchers have looked at this and mutations have been found, but they are different mutations in different cases. This is particularly true of “sporadic” tumors that do not occur in a family. What is also interesting in Cushing’s, is the higher incidence in women. In acromegaly (a GH secreting pituitary tumor) and other types of pituitary tumors, we see more men. We really don’t know why Cushing’s Disease is more prevalent in women than in men.

Dr. Lacroix – There is another way that DNA may play a role. It is known that not everyone with the same coritsol production gets the same symptoms. Cortisol acts on cells in the body by interacting with a glucocorticoid receptor in individual cells. Dr. Steven Lambert’s group in The Netherlands has reported on differences in the glucocorticoid receptor in the general population. They found that very small changes in the DNA of this receptor can alter the activity of the receptor. Most of the population has average receptor activity, but a portion of the population has been shown to have low receptor activity and some of this population does not appear to develop metabolic syndrome, diabetes, hypertension, etc. and on average, they tend to live longer. A small fraction, 5-7%, of the population has more efficient receptors.

Thus with Cushing’s, it could be that a person with Cushing’s who has low efficiency receptors, may not show as many symptoms or symptom severity as someone with Cushing’s who has high activity receptors. This has not been proven with Cushing’s, but perhaps different receptor activities complicate diagnosis as not everyone has the same normal production of cortisol.

Question: What is life expectancy after remission of Cushing’s?

Dr. Tyrell: We published on this back in 2004 with about a 15 year follow up of Cushing’s patients, and had similar results to this type of study from Mass General. The results are that if you can get the cortisol down to normal, life expectancy returns to normal. Studies from Sweden and the UK, indicate that if you are on over 30mg/day of permanent hydrocortisone replacement, mortality increases.

Question: I had to have both of my adrenals out, am now steroid dependent, and considered Addison’s. Is my life expectancy normal?

Dr. Tyrrell: Studies have shown that those with Addison’s have normal life expectancy unless they are over replaced with more than 30mg/day of hydrocortisone. This is true as long as patients understand that they need to increase their dose during times of illness, go to the hospital for serious illness, carry an emergency syringe and wear a medic alert bracelet. If patients follow instructions, they are not at risk of sudden death due to adrenal insufficiency.

Question: Without adrenal glands, do I have a normal fight/flight response to stress?

Dr. Blevins: Yes. Your autonomic nervous system makes plenty of nor-epinephrine (nor-adrenalin) for a normal fight/flight response.

Question: I am 7 months past pituitary surgery and I’m still on 10 mg/day of hydrocortisone. Do I need to be concerned that the replacement is causing further damage to me?

Dr. Tyrrell: No. That is perfectly normal for your stage of recovery. The patients in the study we published were treated for the first year. The concern comes in when people are permanently dependent on replacement hydrocortisone, are never tapered and are on more than 30mg/day for extended periods of time.

Question: I’ve had all of my pituitary gland removed and am on permanent replacement. Do I need to be concerned about 20mg/day of hydrocortisone replacement? I’ve tried to taper lower, but can’t seem to do it.

Dr. Heaney: There is a difference in patients who are in recovery with the idea of eventually tapering off replacement versus those who will be dependent on hydrocortisone replacement permanently. For someone on permanent replacement, 20mg is about the right range. When I was studying in the UK, we commonly replaced with 30mg/day, then it came down to 20-25 mg/day and recently there have been some reports that in some cases, 15mg/day is enough. Of course it is going to vary depending on body size, etc. But in general, 20mg/day should be fine.

Question: Can hydrocortisone cause liver damage?

Dr. Tyrrell: No. We have never seen this.

Question: About how long does it take for muscles to get back to normal and will I be able to do what I did physically before?

Dr. Heaney: I think I was recently reminded just how severe the weakness can be. I have a patient who has recovered, is back to work and says that mentally she is back to normal. She made the effort to gain strength by going to a gym and working with a personal trainer. Before Cushing’s, she was a triathlon runner and reports that she is at about 30% of her previous physical ability and she is 2 years past her remission. So, I think as Dr. Vance covered in her talk, some of the effects of Cushing’s are long-lived and may not return to normal.

Dr. Lacroix: One other point and that is that high cortisol does cause bone loss, often resulting in osteoporosis. This has been studied in patients after remission, and it is clear that bone density can be recovered, but it takes several years. It’s not surprising that something that took years to develop can take a similar amount of time to recover.

Question: We often hear the term “severe” Cushing’s used. How do you tell what is “severe”?

Dr. Vance: It’s a subjective determination. In other words, we have patients who barely look like they have Cushing’s and they function well. We have other patients who can barely walk into the exam room. Dr. Blevins: I don’t have a scoring system, but as Dr. Vance just mentioned, it varies widely from those who barely look like they have Cushing’s to severe cases. For example, I had a patient who was transferred from another hospital and after spending a little time with him, it was clear that his life was in serious jeopardy due to Cushing’s and I really wasn’t sure that he was going to make it. So, Cushing’s can be that severe. Fortunately, he is alive today. Cushing’s does vary widely. It’s kind of a gestalt that the physician develops with experience in assessing the consequences of the disease in a specific patient and how complicated the patient is. Generally, patients with infections have more severe Cushing’s, but that doesn’t always correlate with cortisol levels.

Question: I had Cushing’s many years ago, with a recurrence about 5 years ago. Now, my doctor is suggesting physical therapy. Would physical therapy have been more helpful years ago?

Dr. Vance: I think exercise is a good idea, if you can do it. It’s not necessarily the physical therapy that is useful, it’s the getting up and walking; going to water aerobics is always good because it doesn’t hurt the joints. But, recovering Cushing’s patients have limitations because they hurt so much. Then they try to push it and end up hurting more, which can lead to frustration and more depression. So what I tell my patients is to take it easy during recovery, but gradually try to increase your level of activity.

Dr. Blevins: I agree. Be active and do as much as you can. Keep moving.

Dr. Katznelson: I do push people to do some type of resistance exercise whether it be water aerobics or swimming because Cushing’s is associated with muscle loss and decreased strength particularly around the shoulders and the hips. So, I tell patients they should be getting some form of exercise, but the problem is the limitations. If you have having steroid withdrawal symptoms every time your dose is lowered, which is what we expect to happen, it’s hard because you don’t have the energy and you don’t feel well. So, I tell patients do what you can during recovery and you will be able to do more after you are off the steroids.

Question: What are the long term effects of ACTH on the body?

Dr. Tyrell: The main effect is hyper-pigmentation, which is darkening of the skin. This can occur over the entire body plus the lips, inside the mouth and the tongue. Other than that, there are no quantified adverse effects. Some people have studied ACTH and the precursors and reported that they can actually make your memory better, but I don’t know if that’s really been established.

Question: What is Nelson’s?

Dr. Tyrrell: Up until the 1970′s, the treatment for any kind of Cushing’s was either unilateral or bilateral adrenalectomy. So you had patients with pituitary tumors having their adrenals removed. As was mentioned, anywhere from 5-50% had progression of their pituitary tumor after the adrenalectomy with high ACTH levels and hyper-pigmentation of the skin. As Dr. Weiss mentioned, we now operate on the pituitary first as is appropriate, and get rid of the tumor, or everything except one that is so small that it can’t be seen. A previous speakers slide mentioned that the estimate of Nelson’s is now 8%. We think it is closer to 4-5%. Several patients have asked me about ACTH levels following an adrenalectomy. Your ACTH levels will go up because we give you short acting steroids. So if your ACTH level is 50 to a couple of hundred, that is just normal for having no adrenal glands and does not indicate that you have Nelson’s.

Dr. Vance: The definition of Nelson’s refers to growth of the pituitary tumor that is still there.

Dr. Weiss: Dr. Don Nelson, who first reported this syndrome in 1958, is still alive. His report came at a time when you could report in the New England Journal of Medicine on one patient. You have to remember that Dr. Nelson didn’t have the benefit of MRI or CT scans, and what they reported on was a patient with Cushing’s who had a bilateral adrenalectomy and then got very high ACTH levels. Dr. Nelson was the one who initiated measurement of ACTH. This patient grew a tumor, and this patient probably had a tumor before the adrenalectomy, they just didn’t know it, due to the lack of imaging technology. The bad thing about Nelson’s is not the elevated ACTH, it’s that if Nelson’s develops, they can be very aggressive tumors, they tend to be resistant to radiation, they can metastasize and they can be very difficult to treat. I hope I made the point earlier, that when we find a tumor, we do not do a bilateral adrenalectomy, rather radiation would be the next step to get the tumor under control. But if there is no tumor, we will proceed with an adrenalectomy. I think Dr. Heaney made an interesting comment that perhaps there is a hypothalamic cause of Cushing’s that we don’t know about yet and that may permit us to do an adrenalectomy without causing growth of a pituitary tumor.

Question: I had Cushing’s and have been diagnosed with Rheumatoid arthritis. Are they related?

Dr. Lacroix: It is not uncommon that when patients are cured from their Cushing’s syndrome, that some underlying disease appears. The anti-inflammatory properties of high cortisol levels put some diseases to rest. High levels of steroids are actually used as treatment for a number of inflammatory or autoimmune diseases. I have had patients who developed ulcerative colitis, Chron’s disease, etc., that wasn’t apparent during Cushing’s, because the high steroid levels were “treating” the disorder.

Dr. Vance: Having Cushing’s or high cortisol does not cause Rheumatoid arthritis. Rather, once the Cushing’s is resolved, the underlying disease comes back.

Question: Dogs and horses get Cushing’s and are treated with medication. Have medications used to treat Cushing’s in dogs and horses been tried on humans?

Dr. Tyrrell: The most common medication used to treat dogs is mitotane, or o,p DDT. According to the veterinary experts at UC Davis, dogs tend to tolerate this medication extremely well. People don’t tolerate mitotane very well. It’s almost only used in cases of adrenal cancer and the reason is its toxicity. People generally experience malaise, somnolence, and diarrhea. It was used in France for a while, but it never really caught on as a treatment in North America.

Question: I’m about a year and a half past surgery and most things have resolved, but I still struggle with anger, irritability, shortness of temper and impulse control. Will this improve?

Dr. Lacroix: What the data shows is that there is improvement with time, but as I mentioned earlier, in some cases it can get worse during the first year. At 18 months, it is a little early to project. I think it’s a matter of time. Another point is that for example, if you don’t have a pre-disposition to diabetes, you will not become diabetic with Cushing’s. That is also true with hypertension. There is a range of personalities as well. What is believed is that there is a very good chance that people will go back to whatever they would have been without Cushing’s. Dr. Heaney: I’d just like to add that I often prescribe a dose of a mild antidepressant medication in the immediate post-op period. Commonly these are the SSRI’s, Wellbutrin, Celexa, etc., which can be helpful in getting through the very difficult first 3-6 months. It’s certainly not something that one needs to stay on long term.

Question: I’m back in school and found it harder to keep up with note taking, remembering things and my grade reflected that. I also have anger issues. Is that common?

Dr. Lacroix: I think that patients do notice the cognitive changes and that they are very real, as are mood changes. I think what you are describing is experienced by many Cushing’s patients and has to do with the effect of Cushing’s on the brain. This takes time to recover. I think everyone will say that this improves, but may not recover completely, depending on the degree of the damage that was done.

Dr. Blevins: I think what patients need to recognize, is that they have been through a life threatening illness and their bodies have gone through a great deal of change, both mentally and physically. In that process of recovery, having chronic changes and chronic illness, you will be more irritable. With anger, you could be having a normal response to a given situation. We all have different triggers and the goal is to work with your family to identify those triggers before you are continually faced with them. Dr. Lacroix: We need a multi-disciplinary approach to this disease. Not only do we need the endocrinologists and surgeons, but we need psychologists and psychiatrists. I often refer Cushing’s patients to psychiatrists. Unfortunately, there are patients who commit suicide during the recovery period from Cushing’s. This should not happen and we need to take this very seriously. Like any other medical condition, it needs to be dealt with by experienced professionals. Patients should not feel guilty about the fact that they may need professional help and psychotherapy is something that can be very helpful.

Editor’s Note: On February 27, 2010, the CSRF held a Cushing’s Patient Education Day. Included in that meeting were several panel discussions in which many excellent questions were asked. The above is a transcript of the question and answer period. The presenters were Dr. Lewis Blevins is Medical Director of the California Center for Pituitary Disorders at UCSF in San Francisco, Dr. Anthony Heaney is Co-Director of the UCLA Pituitary and Neuroendocine Program in Los Angeles, Dr. Lawrence Katznelson is Medical Director of the Pituitary Center at Stanford Univ. in Stanford CA , Dr. Andre Lacroix is Professor of Medicine and Director for Medical and Academic Affairs at Centre Hospitalier de I’Universite de Montreal (CHUM) in Montreal, Canada, Dr. Blake Tyrrell is an Endocrinologist in the UCSF Endocrine Group Practice in San Francisco, Dr. Martin Weiss is Professor of Medicine and Martin H. Weiss Chair in Neurosurgery at the Keck School of Medicine at USC in Los Angeles, and Dr. Mary Lee Vance is Professor of Medicine and Neurosurgery at the Univ. of Virginia, Charlottesville . The CSRF is very grateful to all of the doctors who participated in this program.

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