Clinical Features, Co-morbidities and Diagnosis of Acromegaly.

CARLOS R. HAMILTON, JR., MD, FACE: Hello, and welcome to the AACE Clinical Conversations. I'm Dr. Carlos Hamilton. Today we'll be discussing the clinical features, comorbidities and diagnosis of acromegaly. Joining me today is Dr. David Cook, Professor of Medicine at Oregon Health and Sciences University, and Dr. Lawrence Katznelson, Associate Professor of Medicine at Stanford University School of Medicine. Welcome. Thank you for being here.

Acromegaly is a clinical syndrome resulting from excessive growth hormone secretion, almost always due to a pituitary gland adenoma. Dr. Cook, what is the incidence and distribution of this disorder, in your experience?

DAVID M. COOK, MD: There are about three or four new cases per million population per year, and the prevalence is around 60 per million. And they're equal sex distribution, male and female, and the average age at diagnosis is age 44. This seems to be worldwide. There's no prevalence or increased incidence than any other country, so pretty much universal prevalence and incidence.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Katznelson, it's widely known that acromegaly may be present for many years before the diagnosis is actually established. How much of a delay is common in making this diagnosis?

LAWRENCE KATZNELSON, MD: You are right to say that this is an often-delayed diagnosis. Patients often have acromegaly for at least five to ten years before diagnosis is made. And the reason is that, because this is a very slow-growing, insidious type of disease, and there are clear, dramatic changes that can occur on the face, other aspects of the body.

When someone's looking at themselves in the mirror every day, they don't see these relatively slow-changing effects upon the body. So what happens is, this diagnosis is often made when someone sees a new physician or sees a long-lost relative or an old friend.

In fact, the most common presenting finding for women are irregular menstrual cycles. So in men, it could be headaches or is picked up, again, incidentally.

CARLOS R. HAMILTON, JR., MD, FACE: Are there signs and symptoms that could point to the diagnosis earlier if we were more aware of what they might be?

LAWRENCE KATZNELSON, MD: Yes. The classic signs and symptoms include growing hands and feet, changes in the face, large tongue, growing jaw. And there are other signs, including diabetes and hypertension.

Now, again, patients often don't describe these to their physicians, and so the diagnosis is not made. But physicians should be aware that if a patient has new onset hypertension or difficult-to-control diabetes, they should be thinking about the diagnosis, and maybe that would lead to earlier diagnosis.

CARLOS R. HAMILTON, JR., MD, FACE: I was interested in one of the papers that I believe you wrote, that you had mentioned that one of the early signs and symptoms of this condition can be sleep apnea or can be excessive sweating. Are these things that we ought to be looking for in patients that present with these complaints?

LAWRENCE KATZNELSON, MD: Yeah, sleep apnea syndrome is very common in patients who have acromegaly. For patients who have acromegaly and snore, it is almost universally present. Even if they're not snoring, it's very common. So we often recommend to sleep clinics that if a patient presents with snoring, they should think about this diagnosis and draw the appropriate test. The same goes for excessive sweating, as well. This is a very common presentation of acromegaly.

CARLOS R. HAMILTON, JR., MD, FACE: We understand, Dr. Cook, that acromegaly is associated with an excessive mortality. Tell us a little bit about that, and what is the significance of that?

DAVID M. COOK, MD: Yes, the excessive mortality, when left untreated, basically is a cardiovascular mortality. So increase not so much in heart attacks, but stroke and cardiovascular deaths. There are a number of factors that lead up to this increase in cardiovascular risk.

So growth hormone plays a big role in the context of heart muscle. So you have a hypertrophic cardiomyopathy, you have acceleration of cerebrovascular disease, you have an increased cholesterol total and LDL and diminished HDL. And then one of the big impacts, of course, with growth hormone is it interferes with insulin action, so you actually develop insulin resistance and in 40% of the cases, frank diabetes or impaired glucose tolerance.

CARLOS R. HAMILTON, JR., MD, FACE: So vascular disease is the principal cause of the excessive mortality in these patients. Is that your experience, Dr. Katznelson?

LAWRENCE KATZNELSON, MD: Yes. The heightened mortality risk appears to be due to both cardio and cerebrovascular disease.

CARLOS R. HAMILTON, JR., MD, FACE: Now, what about the incidence of malignancy in this? You would think that growth hormone-stimulating growth might make malignancy as a more common condition. Has that been borne out?

DAVID M. COOK, MD: That's really controversial. If there is an increased incidence in malignancy, it's colon cancer. There is a clearcut association of increased colon polyps, and of course we know that is a precursor to the potential development of colon cancer. But to have an actually increased incidence of colon cancer is probably not true.

It is true, however, that if colon cancer occurs in an acromegalic patient that is untreated, it has a very virulent and rapid course.

CARLOS R. HAMILTON, JR., MD, FACE: Very interesting. I have seen several patients with acromegaly in whom hypertension was really a rather significant factor. Is that a common finding in patients with acromegaly?

DAVID M. COOK, MD: Hypertension is very common in acromegaly, and that's one of the points that you brought out, when some of these features start to add up, poorly controlled or difficult-to-control hypertension, diabetes, arthritic problems, sleep apnea, as Dr. Katznelson pointed out, then we should start thinking of the possibility of acromegaly.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Katznelson, a number of patients that I've seen, and I'm sure others, with acromegaly have had very large pituitary adenomas. Does that tend to be a matter of the timing, or is that something characteristic of growth hormone-secreting adenomas?

LAWRENCE KATZNELSON, MD: Yes. At diagnosis, approximately 70% of tumors are called macroadenomas, which means they are greater than 1 cm. And this is thought to be due to a combination of factors, the main one being the delay of diagnosis. So if patients have had a delay of diagnosis by at least five to seven years, then they presumably had the tumor well before that time period. Then there's many years to allow for these benign tumors to grow, and they are benign.

Well, there are cases that have been described in young patients that the tumor appears to be more aggressive and grow faster. In terms of the risk of apoplexy, which means hemorrhage into the pituitary tumor, that does not appear to have any strict age course, and can be found in older and younger patients, as well.

CARLOS R. HAMILTON, JR., MD, FACE: Now, one of the things that we're very interested in is in how one goes about establishing the diagnosis of acromegaly. Dr. Katznelson, tell us a little bit about the laboratory diagnosis of this disorder.

LAWRENCE KATZNELSON, MD: Sure. The pituitary gland makes growth hormone, and acromegaly is due to a pituitary tumor that's making excessive growth hormone, and the growth hormone is secreted in pulses through the day. So our random growth hormone level is of little use unless the level comes back exceedingly high, so we have other tests we have to confirm the diagnosis. A glucose tolerance test can be performed where following administration of the oral glucose, growth hormone levels are measured over the next two hours, and a trough level means a lowest level in a normal, should fall to less than 1 (ng/mL). A level that does not fall to 1 (ng/mL) is consistent with hypersecretion of growth hormone or acromegaly.

The other test is measurement of IGF-1, which stands for insulin-like growth factor 1. This is produced by the liver in response to the growth hormone, which is circulating and causes production of IGF-1. And IGF-1 is an integrated marker of growth hormone. So a random IGF-1 level drawn any time of the day, if elevated, can be very well consistent with the diagnosis, as well.

So the two tests we have are an oral glucose tolerance test looking for incomplete suppression of growth hormone, and an IGF-1 level, which is adequate, as well, in the setting of a patient who appears to have the clinical diagnosis of acromegaly.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Cook, would you agree, then, that the IGF-1, as a test that you can do under any circumstances, is a good screening test for patients with acromegaly?

DAVID M. COOK, MD: It's an excellent screening test. The only false positives we might see with that would be puberty and pregnancy, the two P's, so to speak.

CARLOS R. HAMILTON, JR., MD, FACE: We talk about the IGF-1 level having normals that are age-dependent. This age variation is largely during a child's growth and the puberty years. In adulthood, is there much of a change with age? Does it change, as one gets older?

DAVID M. COOK, MD: Yes. Basically, starting at age 20, there's a 13% per decade decrease in growth hormone secretion, which is directly reflected in IGF-1 concentration. So it will also diminish as we age, so there are gender and age-published normals for the good assays that are measuring IGF-1.

CARLOS R. HAMILTON, JR., MD, FACE: Now, the measurement of growth hormone, you mentioned, Dr. Katznelson, doing this, during a glucose suppression test to see if it suppresses to less than 1 (ng/mL) in the serum, are there situations in which active acromegaly can be associated with relatively low or even normal levels of growth hormone in the blood?

LAWRENCE KATZNELSON, MD: Yes, there are situations that we need to consider in terms of assessing the measurement of growth hormone. Growth hormone levels can be relatively elevated, and patients who are malnourished or who have liver disease or kidney disease. Eating disorders can be associated with an elevated growth hormone level. Diabetes mellitus, if there is involvement of liver with fatty infiltration, can cause an elevated growth hormone level, so we can see false positives in that respect, in measuring growth hormone.

Growth hormone levels can be lowered in patients who are overweight or have significant diabetes itself, just elevated glucose levels. So we need to consider these situations when we are assessing and interpreting the growth hormone measurements.

CARLOS R. HAMILTON, JR., MD, FACE: The measurement of growth hormone, of course, it's an immunoassay type -- type procedure. Are there situations in which sometimes we can get misleading results from this as a result of the biology of growth hormone, or for other reasons?

LAWRENCE KATZNELSON, MD: There are issues with the measurement of growth hormone. There are multiple assays available to us, and each commercial assay tends to be somewhat different, and normal -- different ranges in different assay sensitivities.

So our ranges have changed over the years, and therefore interpretation of growth hormone values to assess treatment strategies, as well.

CARLOS R. HAMILTON, JR., MD, FACE: Now, one of the things that we -- one would do if you had suspected the diagnosis and then had established the diagnosis in the laboratory would be to do some imaging procedures to try to identify the presence or absence of a pituitary adenoma. Tell us a little bit about what procedures you would order for a patient under those circumstances.

DAVID M. COOK, MD: Well, by far the procedure of choice would be a pituitary MRI, and that's the way the physician should order that. Not a head MRI, which would not give you the views specifically of the pituitary area. So a pituitary MRI with and without gadolinium.

I don't think you need a dynamic MRI. As Dr. Katznelson has pointed out, most of these tumors present as macroadenoma, and what we really want to know is the limits of the tumor, not so much finding a small tumor. So pituitary MRI, not CAT scan, which is very insensitive in this area, with and without gadolinium.

CARLOS R. HAMILTON, JR., MD, FACE: But doing an MRI specifically of the pituitary gland makes the radiologist able to give us a much better interpretation and a better diagnosis. Is that correct?

DAVID M. COOK, MD: That's correct.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Katznelson, if one does an imaging procedure, an MRI of the pituitary gland in a patient that we are quite sure has acromegaly and you do not find an adenoma, what might that indicate?

LAWRENCE KATZNELSON, MD: Well, over 95% of patients with acromegaly have a pituitary adenoma as the cause of the growth hormone hypersecretion. There are rare cases of ectopic secretion. There have been several cases of growth hormone secretion from lymphoma or from pancreatic malignancies. And there have been also a handful of cases of neuroendocrine type tumors that produce growth hormone-releasing hormone.

So the next step would be to do imaging studies to look elsewhere in the body for either neuroendocrine tumors, which is a carcinoid tumor, or pancreatic tumors with usually some -- either a CT or MRI scan of the chest and abdomen, maybe an octreotide scan to look for a neuroendocrine-type tumor.

If these come back negative, then I usually recommend going straight to pituitary surgery, so we often still see a very small adenoma. But we usually go through the sequence of tests just to make sure.

What generally happens is that if patients are not found to have a mass anywhere else in the body, it is usually not subtle, these lesions that are going to be causing growth hormone or GHRH hypersecretion. We usually go straight to surgery.

Of note, patients who have ectopic production of GHRH, which is growth hormone-releasing hormone, usually have a large sella. They have hyperplasia of the growth hormone-secreting somatotroph cells. So the pituitary gland is generally enlarged. So the GHRH-secreting ectopic tumors usually do not have the normal pituitary MRI scan.

CARLOS R. HAMILTON, JR., MD, FACE: Well, thank you very much. I think this has been a very helpful discussion of the clinical features and the comorbidities, and the diagnosis of this very interesting clinical syndrome of acromegaly. Thank you very much for being with us, and thank you for watching. We appreciate your support. Thank you so much.