This week's Grand Rounds: You'll want to read it!

Running a hospital: Grand Rounds -- When things go awry is the name of this week's Grand Rounds post. Paul Levy, President and CEO of Beth Israel Deaconess Medical Center in Boston, is known for his stance on transparency within the medical community. He is also known as "A man with a heart". His topic for the week certainly goes along with that.

In the spirit of Dr. Ernest Codman, I asked doctors, nurses, and other providers to write about incidents in which they made or were present for a medical error. What were the circumstances, and what did you do in response to the situation? How did you feel about the event, and how did it change your practice of medicine afterward.

Likewise, I asked patients who have been the victim of, or loved-ones who have seen, clinical harm to tell their stories. How did your provider(s) respond, how has the event has changed your view of the practice of medicine, and what advice you would give to the profession?

Take some time to peruse and read the his post, visiting all the links from the contributors. They are well worth reading. Make a comment, too, if you wish.

Cushing's Syndrome in Women With Polycystic Ovaries and Hyperandrogenism

Cushing's Syndrome in Women With Polycystic Ovaries and Hyperandrogenism continues the theme of how to distinguish between PCOS and Cushing's. Above is a picture of a woman who was diagnosed as having PCOS. 7 years later, she was re-tested and found to have Cushing's Syndrome instead.

Cushing's patients are frequently misdiagnosed with PCOS. It is an easy diagnosis (in layman's terms) and avoids the multiple tests and confusion which suspicion of Cushing's seems to bring. This article talks about the aforementioned case and 3 others where Cushing's was misdiagnosed as PCOS. Once treated for the Cushing's, all symptoms which had been attributed to PCOS resolved.

The authors make the case for "the diagnosis of PCOS only when other etiologies have been excluded." They also contend " economic pressures drive health care to be delivered within fewer consultation sessions outside of specialist centers [making it] pertinent to emphasize that not all cases of hyperandrogenism or ovarian cysts are related to PCOS and that curable causes, such as Cushing's syndrome, must be excluded by careful history taking, examination and (potentially repeated) investigation."

And, as a sidenote, the authors mention screening patients who have type 2 diabetes. According to them, "Recent data obtained by screening individuals with type 2 diabetes suggest that cortisol excess, widely considered a rare endocrinopathy in the form of classical Cushing's syndrome, is in fact more common than supposed. "

A neverending story....maybe....

Part I: A Neverending Story

I really am not a doctor basher. Oh dangit...I don't want to be, anyhow. But I know I'm not the only one who seldom finds a doctor who sees the whole picture. Yes, it's "just" a sinus infection. But it's more than that to me. Here is the letter I wrote today about my experience, with names hidden to protect the not-so-innocent:

I am a patient of Dr. M. This is not about her. However, I did see her on June 13 for a sinus infection which included a very bad headache and sore, painful areas below and above my eyes which worsened when I chewed, plus pain all the way to the back of my head. She did concur and prescribed 5 days of levaquin. Since I had transsphenoidal endoscopic surgery to remove a pituitary adenoma several months ago, a sinus infection is doubly concerning. I have fought sinus infections for years, and use preventive measures. However, I feel I need to be seen by a professional when I can’t get rid of it or control it with no antibiotics.

The levaquin did work for me, but it took about 4 days before my sinuses loosened up enough for a little of the “crud” to start coming out. I went out of town for several days, and returned late yesterday (Friday). My sinuses have closed back up, are very painful, and my terrible headache is back. I thought it would be better to see someone today rather than wait until Monday to try to catch this before it got worse. I felt like, and still feel I did not have a long enough course of antibiotics. I am not trying to play doctor, but I do know how my body acts and am not stupid.

I saw Dr. X at the urgent care on ***** Avenue. I went there because it is also where Dr. M works during the week and thought it would be a continuance of care rather than starting all over. Dr. X said my right sinus was very congested and my left was fairly congested. However, since the levaquin didn't work, he said it had to be viral and I needed to use Flonase. I refused the Flonase and told him I knew I could not use it but could not remember why. He then wanted to put me on sudafed and steriods. I politely refused both telling him I could not take the sudafed due to blood pressure issues and I was already on steroids due to adrenal insufficiency from my pituitary surgery. I am trying to wean off of those, but adrenal insufficiency, especially when magnified by an infection, makes it tough. Well, he was very unfriendly/antagonistic, did not want to listen to my explanation, and told me I could just wait and see Dr. M. I was in tears. I told him the levaquin was starting to work, but I just needed a longer dose, I thought. He said I didn't need to "just be taking antibiotics to see if they might work". I was furious but courteous. I told him that I never "just took antibiotics" and took very few of them compared to most folks. He was not interested in any of my history. He walked out on me! He said, "You can get dressed and leave." I was never discourteous and I did not deserve that type of management.

As for the Flonase, GlaxoSmithCline, Inc. include the following in their studies:

Like any other nasally administered corticosteroid, acute overdosing is unlikely in view of the total amount of active ingredient present. However, when used chronically in excessive doses or in conjunction with other corticosteroid formulations, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of
fluticasone propionate should be discontinued slowly, consistent with accepted procedures for discontinuation of chronic steroid therapy (see DOSAGE AND ADMINISTRATION).

(As a sidenote: All the studies of the effects of Flonase on the HPA-axis have been done with “normal” patients, not those with a compromised HPA-axis and/or Cushing’s Disease.)

I do not want to mess with my HPA-axis more than I have to. The repercussions are normous and obviously not understood by Dr. X. I am already dealing with a tenuous balancing act trying to replace all the hormones lost due to a pituitary adenoma that was not caught for over 20 years. (Thank you, Dr. M for saying “endocrine” to me when I first saw you.) Each of these affects the other, and adrenal insufficiency is just one price I pay if these aren’t balanced properly. I realize this is a lot to understand in one office visit, but he should have treated me with more dignity and understanding. And he could have listened.

GlaxoSmithCline also says that Flonase is contraindicated with viral infections (which Dr. X said I probably had), yet he wanted to put me on it. I am at a loss to explain this, but perhaps would understand if he had taken the time to explain.

To summarize, I am in pain, will have no treatment until Monday when I can reach Dr. M, and I feel Dr. X was out of line.

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Part II: Persistence Pays

I used to invariably expect the best from people, and that included doctors. I used to wear rose-colored glasses. Now, I invariably hope the best but expect the worst. But every now and again I get fooled. Today was one of those days.

After writing that letter, I hung over a steaming pot, took ibuprofen and mucinex, and prayed to the steam gods to loosen my sinuses so I could sleep. The next morning, with the feeling of umpteen hangovers I was wondering when the party ever started. When my phone rang, I contemplated ignoring it, but did pick it up.

"This is [Lulu]. Dr.M wants to know if you can come in this afternoon. She's double-booking just so she can see you. She got your fax."

"What fax?" (Did I send that in my stupor??)

"The fax you sent about your visit to the doctor on Saturday."

"I didn't send a fax."

"Will you hang on a moment?"

As I was "hanging on" it dawned on me. Ah ha! SOMEONE had sent it. I suspected the recipient of the letter who works for customer service in the medical organization to which the urgent care belongs.

She returned. "Yes, well, Dr. M. is talking about you. She said she got the fax and it's about you. Can you come in this afternoon?"

"I'll be there."

I did go, wishing I had a chauffeur so I could close my eyes against the glaring sun. Oh, my pounding head. Dr. M was a dearheart. She apologized mightily for Dr. X's treatment of me and said, "Off the record, we've had a lot of complaints about him." She professed delight in my letter. I hope she wasn't trying to make me feel better. No, I think she really meant it. BTW, I got a big hug from Dr. M to go with it. She does hug....that's good medicine, too.

A shot of rocephin, two prescriptions for 14 days of levaquin and some percocet later, I was off to sell my soul to Walgreens. Since it took 45 minutes, I found a cup of Starbucks and a place to rob wireless internet while I waited. Oh my aching head. (Have I said that already?)

I'm hoping my letter does some good, but I'm doubtful. I was even second-guessing myself after writing it and asked my good friends if I was over-reacting. I asked my parents the same thing. They assured me I wasn't, but that's what chronic illness does. It beats us down to the point we are almost apologizing for being ill, and then when we do react...well, we second-guess our reactions.

I have dreams of educating our local medical profession about my type of illness, but then reality hits when I meet a Dr. X. How do I overcome that God complex? And where do I find the energy? How do I make them read the new research? And frankly, how much time do they really have for that? The Doctor Will See You for Exactly 7 Minutes....

My head is still pounding. I just took a percocet. I hope it helps. Wonder if I should send Dr. X one?

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These were originally posted on June 21 and June 23, 2008, respectively. I wanted to include them in Grand Rounds which has a theme this week, so am posting them together again. Thank you for your understanding.

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Distinguishing PCOS and Cushing's: Does testosterone tell the tale?

Cushing's Syndrome (CS) has been considered rare, but thoughts are changing about that. This article notes that fact, pointing out "most published articles on CS have examined patients with sustained and severe hypercortisolism." It also points out the increased recognition of the prevelance of "mild" and "episodic" CS which have both normal and high values with testing. (Image source)

CS and polycystic ovarian syndrome (PCOS) present similarly, but are treated much differently.

Both diseases can present with weight gain, hirsutism, acne, and irregular periods in women. However, CS usually includes symptoms such as easy bruising, sleep disturbances, decreased libido, a buff alo hump, and stretch marks, which are not present in PCOS. Women with mild and/or periodic CS, however, can be difficult to diagnose as they may lack classic manifestations of the disease and the diagnosis may require multiple hormonal measurements [4, 5, 7] . The treatment of CS is primarily the surgical removal of a pituitary, adrenal, or ectopic tumor. The treatment for PCOS is primarily medical and includes oral contraceptives, biguanides (metformin), thiazolidinediones (rosiglitazone or pioglitazone) or androgen antagonists (spirolactone or flutamide) [8] . Thus, distinguishing the two conditions is important.

This study used women who, under the 1990 NIH criteria, have PCOS. These were compared to women who had been diagnosed with mild CS due to a pituitary adenoma. The study goes into great detail about the criteria for each set.

The authors hypothesized "either total testosterone (TT) or bioavailable testosterone (BT) levels or the calculation of the free androgen index (FAI) would be low in patients with mild CS and elevated in patients with PCOS, and could help differentiate the two conditions." According to their statistical analyses:

Total testosterone gave the highest sensitivity, positive predictive value (PPV)and negative predictive value (NPV) while BT gave the highest specifi city for the diagnosis of CS. Determinations AUC demonstrate that use of a TT level gave “ good ” diagnostic accuracy, while BT and FAI gave “ fair ” diagnostic accuracy.

The authors emphasize "[m]ost commercial assays lack the accuracy and precision of assays when measuring testosterone in women, as recently reviewed in an Endocrine Society position statement [35]". They used mass spectroscopy analysis done at Esoterix Laboratories. They also determined there is overlap between the two groups when dexamethasone suppression is used due to the mild/cyclic nature of these CS patients. Most of all, the phenotypes between the two groups may be similar. Testosterone analysis, when using an accurate and precise assay at a validated laboratory, may be another tool to distinguish between the two.

Note: There are some great graphs and charts in the full-text article. It is well worth perusing. My previous post has some of them included in the first scribd presentation by Dr. Friedman.

Pall, M., Lao, M., Patel, S., Lee, M., Ghods, D., Chandler, D., & Friedman, T. (2008). Testosterone and Bioavailable Testosterone Help to Distinguish between Mild Cushing's Syndrome and Polycystic Ovarian Syndrome Hormone and Metabolic Research, 40 (11), 813-818 DOI: 10.1055/s-0028-1087186

Diagnosing and Treating Cushing's: Presentations by Dr. Theodore C. (Ted) Friedman

Dr. Friedman's original PowerPoints may be found at his website. These are very informative and easy to follow.

Publish at Scribd or explore others: Health & Medicine Research tumor adrenal

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Publish at Scribd or explore others: Research tumor adrenal

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Publish at Scribd or explore others: Research tumor adrenal

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Publish at Scribd or explore others: Research tumor adrenal

Attitude, part three

A lot has changed since I wrote Attitude, part two . Actually, I guess in some ways much is still the same, but information I now know has changed.

Have you ever had one pivotal moment in your life which may seem fairly innocuous to others but was life-changing for you? Something that would wouldn't make most folks even raise an eyebrow, but you knew it meant something important for your future? Your now?

Yes, I had one of those moments this week. All because of a urinary free cortisol (UFC) test. It was high. Not just a teeny bit high. High. Heart-wrenching, gut-churning, stop-the-presses high.

Actually, I wasn't shocked. You see, I have had a heck of a time weaning off of hydrocortisone since my pititary surgery in 2006. Adrenal insufficiency followed me like a hound on the trail of racoon, sniffing my heels when I tried to wean. With a lot of effort I had managed to finally get down to 5 mg of cortef consistently by the time I posted Attitude, part two . Because of a change in growth hormone doses and thyroid replacement levels about that time, it was even tougher to stay that low. Both of those need sufficient cortisol to work well and will use what's available. But all of a sudden, I felt "Cushie" on the 5 mg. So I easily weaned to 2.5. Then, I felt Cushie on that, so I stopped it.

Sure, I had a few "tough" days. But I weathered through them. My body wanted what it was used to. But no adrenal insufficiency prevailed. My endo had ordered the UFC to check my levels while on cortef, but since I had managed to wean off prior to doing it, it showed my natural levels, not supplemented levels.

Typically I get results as soon as they are run, but we forgot to put that permission on this slip, so I had to wait on my endo's office to send them. The fact I didn't raise cain or have a conniption fit in order to get them myself is testament to the fact I knew in my heart what the result would be. I was in denial. I didn't want to see that. I wanted to stay in remission. I want to be cured.

I got a brief email with the results. I opened the email, clicked on the PDF attachment, and there it was in black-and-white.

High.

My world changed. I cannot change it back. I can't go on in blissful ignorance thinking I may still have a cure. That I may still be in remission. The question mark is now there. And it is a huge one.

So, what do I do now? I test. And test some more. Until we have a definitive answer. MRI's, midnight serums, midnight salivaries, more UFCs. I know those are coming. Wait, they are here. Now I do them.

Life changes.

The Blunting of Occam's Blade: Why diagnosis is less important in endocrinology in the 21st century

During the second BlogTalkRadio interview of Dr. Theodore (Ted) F. Friedman, he talked about something he had written. He gave me permission to share it:

With permission from Dr. Friedman:

In the 14th century, William of Occam stated, "Plurality must not be posited without necessity." This led to the concept populated by the famous internist, William Osler, who posited that each patient should have one disease, and that disease can explain all the patient's symptoms. In medical school, young physicians learn this philosophy and continue that philospophy throughout their medical career. They often look for a single, unifying diagnosis in each patient and expect that all the patient's problems are related to this single diagnosis. When that diagnosis is treated with a standard treatment, the problems should go away. Dr. Friedman feels this philosophy of Occam's Blade is detrimental to modern medicine, especially endocrinology.

Patients are becoming increasingly complex and have multiple subtypes. It is important to distinguish between the subtypes, as that may alter treatment. Additionally, not all patients with a single disease present similarly. For example, patients with Cushing's syndrome may manifest diverse symptoms including weight gain, trouble sleeping, severe fatigue, decreased libido, high blood pressure, and diabetes, but most patients with Cushing's syndrome do not have all of these conditions and they only have a few of them. Many physicians only know about Cushing’s syndrome from a picture of a severe Cushing’s syndrome they see in a textbook and may say to a patient that they don’t have Cushing's syndrome, because they lack one or more signs from that textbook case. Therefore, it is important not to lump everyone together with a diagnosis of Cushing's syndrome but rather to recognize that there may be different subtypes. This is especially important in the field of diabetes, which can be due to problems such as insulin resistance, lack of insulin production, inflammation, or problems with glucose disposal. Currently in diabetes, all patients are treated with similar medicines regarding of their etiology of diabetes. Dr. Friedman expects this to change in the near future, and subtyping patients will become standard of care. Additionally, recognizing that patients with a single disease may have different manifestations of that disease is becoming more prevalent.

While Dr. Friedman does like to try to provide a diagnosis to the patient, but sometimes it is more important to recognize a symptom complex that can be treated with different medications. Many diseases, such as polycystic ovarian syndrome (PCOS), are really grab-bags of different symptoms put together. Therefore, diagnosing someone with PCOS just means that other causes of the symptom complex of weight gain, extra hair growth and irregular periods, have been excluded. Dr. Friedman does not find it particularly useful to give someone a diagnosis of PCOS but rather to treat those initial symptoms and find out whether they are due to a laboratory value such as high testosterone that can be corrected with medications.

Hopefully Occam's Blade will be put to rest and more symptom- and laboratory-based specific treatments will come to the forefront of endocrinology in the future.

What's the real deal about Metabolic Syndrome?

The other day Dr. Rob, who blogs at Musings of a Distractible Mind, tweeted about a patient he had seen that day. He asked for input and wow, did he get it! I promised some information via this blog a the end of the discussion. Thus, this post, which will continue after the dialog.

To get the gist of the dialog, you must start at the bottom and read up. I may have missed some tweets about his original statement and I apologize if so. I tried to find them all.

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staticnrg
04:33 PM Mar 06, 2009
@doc_rob I'll include this, too. I'm loaded for bear. ;) (reference to PCOS statement made by doc_rob)

staticnrg
04:32 PM Mar 06, 2009
@doc_rob Too much to tweet about. Will blog about it and post URL this weekend.

doc_rob
04:28 PM Mar 06, 2009
@staticnrg I can see how Low-grade cushings will present as Met Synd. That does not = Metabolic syndrome is low-grade cushings.

doc_rob
04:27 PM Mar 06, 2009
@staticnrg Skeptical. Show me the research. Genetics strongly tied to type 2 DM. Related to Polycystic ovaries as well.

staticnrg
04:25 PM Mar 06, 2009
@doc_rob No...beg to differ. Remove cause of hypercortisolism which causes met syndrome (insulin resistance). Treat cause, not symptom

doc_rob
04:21 PM Mar 06, 2009
@staticnrg Perhaps, but for practical purposes, the treatment is to use a "typical" Metabolic syndrome approach. Insulin resistance is root

staticnrg
04:19 PM Mar 06, 2009
@doc_rob Research now says met syndrome a symptom of subclinical Cushing's

doc_rob
04:14 PM Mar 06, 2009
@staticnrg Seeing all comers (as I do), Met. Syndrome is REALLY common. At best, cushings is 1% of the cases.

staticnrg
03:51 PM Mar 06, 2009
@doc_rob Blunt again: statistics are wrong, but slowly being changed. New research/literature does that.

doc_rob
03:50 PM Mar 06, 2009
@staticnrg Yeah, but most metabolic syndrome is hyperinsulinism due to wt, etc. If he was 50, I'd just assume - Just statistic likelihood.

staticnrg
03:48 PM Mar 06, 2009
@doc_rob Gonna be blunt: metabolic syndrome is a catch-all. Many w/Cushing's get shunted into that. You are wonderful PCP for testing. :)

staticnrg
03:40 PM Mar 06, 2009
@staticnrg Have articles if you want them. Can email.

doc_rob
03:36 PM Mar 06, 2009
@staticnrg Normal K (was talking about Conn's - Aldosterone Deficiency). I do Urine Metanephrines for pheo screening. - Follow UpToDate rec

staticnrg
03:27 PM Mar 06, 2009
@doc_rob @ARUPlabs has great site for tests. http://bit.ly/1upxeW

doc_rob
03:36 PM Mar 06, 2009
@staticnrg Normal K (was talking about Conn's - Aldosterone Deficiency). I do Urine Metanephrines for pheo screening. - Follow UpToDate rec

staticnrg
03:27 PM Mar 06, 2009
@doc_rob @ARUPlabs has great site for tests. http://bit.ly/1upxeW

laikas
03:27 PM Mar 06, 2009
@doc_rob Googling 4 Pheochromocytoma + glucose + triglycerides gives many results: http://is.gd/mcjU - just confirms. Will look up Williams

staticnrg
03:24 PM Mar 06, 2009
@laikas @doc_rob Pheo has to be caught when "on". Test for plasma free metanephrines, I believe.

staticnrg
03:21 PM Mar 06, 2009
@doc_rob What @laikas said. I could have "normal" K (low end), then days later have very low K and end up in ER. Other hormones off?

laikas
03:20 PM Mar 06, 2009
@doc_rob But Elevated blood glucose level + high triglycerides (+HBP of course) occur in Pheochromocytoma. Wikipedia :) : http://is.gd/iQ8y

laikas
03:16 PM Mar 06, 2009
@doc_rob Bc of storage of K in muscles low K doesn't always show in blood until a late stage. =safeguard. Almost never abnormal Na in Conn.

doc_rob
03:11 PM Mar 06, 2009
@laikas Conn's yes, but BMP with normal Na, K. makes mineralcorticoid less likely.

doc_rob
01:59 PM Mar 06, 2009
@cushings Well, cushings certainly needs to be ruled out in this circumstance. I think of my cushings pals when I see things like this.

cushings
01:56 PM Mar 06, 2009
@doc_rob sounds like Cushing's in dogs again! Hope he doesn't have it

KidneyNotes
01:31 PM Mar 06, 2009
@doc_r0b Sounds like someone taking prednisone, an unlikely drug of abuse.

KidneyNotes
01:29 PM Mar 06, 2009
@doc_rob Renal artery stenosis...

doc_rob
01:26 PM Mar 06, 2009
@joemd Thanks.

joemd
01:21 PM Mar 06, 2009
@doc_rob Got it. Urine tox screen might help. Love your avitar. :-)

doc_rob
01:19 PM Mar 06, 2009
@joemd This is not real acute - New patient here a month ago with abnormal labs. Today came in with higher BP. Seen by Nephrology alreday

joemd
01:18 PM Mar 06, 2009
@doc_rob Other possibilities: migrane, ruptured aneurysm, other CNS stuff. Head CT? MRI?

joemd
01:17 PM Mar 06, 2009
@doc_rob Yes (cocaine, etc.). Also can see serotonin syndrome with antidepressants (SSRIs, SNRIs, Tricyclics...). Also EtOH w/d

doc_rob
01:14 PM Mar 06, 2009
@joemd None. I am also wondering about drugs.

joemd
01:13 PM Mar 06, 2009
@doc_rob Is he on an antipsychotic (metabolic syndrome)? If so, neuroleptic malignant syndrome?

doc_rob
01:12 PM Mar 06, 2009
not fur, for - he does not have Fur cushings.

doc_rob
01:11 PM Mar 06, 2009
Workup includes Check fur cushings, insulin resistance, renal problems. Anything I am missing?

doc_rob
01:10 PM Mar 06, 2009
Teenage boy with HTN, Headache, Elevated Blood Sugar, Triglycerides - Metabolic Syndrome picture. Strong genetics, but BP very high.

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My intent with this post was to verify for Dr. Rob and others what I said briefly in my tweets. However, it has evolved into so much more than that. I have tried to be as brief as possible yet give enough concrete information (with resources) to validate my statements.

A brief history of the term "metabolic syndrome" helps one to understand the rest of the post. Dr. Gerald Reaven (Stanford University) proposed the “syndrome X” concept in 1988, but the term "Metabolic Syndrome" was coined in 1998 by the World Health Organization, and thus made popular.

In The Metabolic Syndrome: Time for a Critical Appraisal (Joint statement from the American Diabetes Association and the EuropeanAssociation for the Study of Diabetes), the popularity of the terminology is explained:

It has been defined and institutionalized, principally by the World Health organization(WHO) (26) and the Third Report of the National Cholesterol Education Program’s Adult Treatment Panel (ATPIII) (27,28), albeit with different definitions. In addition, other organizations have developed similar, but again not identical, definitions (29,30). The fact that a version of the metabolic syndrome has its own ICD-9 code (277.7) also suggests that it is well thought out (31,32).

However, the article continues with explanations of how this happened and reasons why the term is not a valid one:

In summary, the attempt to define themetabolic syndrome as the result of a single (or even major) unifying pathophysiological process, e.g., insulin resistance, is problematic. Although insulin resistance or hyperinsulinemia is clearly an important feature of the syndrome, many other as yet unidentified factors are also important. Insulin resistance may simply be one of many abnormalities linked to a more fundamental, truly unifying pathophysiology. Moreover, the definition of the syndrome includes risk factors that are only weakly related to insulin resistance or hyperinsulinemia (e.g., blood pressure) and excludes others that are closely related(e.g., CRP, adiponectin). Finally, although many clinical values are significantly associated with insulin resistance/hyperinsulinemia, the strength of their association (which has not exceeded acorrelation coefficient of 0.7 and is usually0.3– 0.6) is not
particularly impressive.

As the article continues, the authors show how there is little to no valid data to show how the old or new definitions actually have any benefit to the diagnosis and treatment of patients. In fact, they contend there is "much fundamental, clinically important,and critically missing information about the metabolic syndrome ...a presumed disease that does not stand on firm ground. [P]atients with diabetes or clinical CVD should be excluded from the case definition of metabolic syndrome, as they provide no additional understanding of risk or treatment recommendations that are otherwise not currently recommended."

According to Clinical Use of the Metabolic Syndrome: Why the Confusion? , there several factions vying for the conclusive definition of metabolic syndrome. The issue, though, is the change of the terminology from a pathophysiological approach to a clinical definition defined by an ICD-9 code (277.7). With multiple factions offering different perspectives, the article offers a requiem, "given the seemingly arbitrary clinical definitions and the uncertain clinical utility, the metabolic syndrome should be declared dead".

Even Reaven, who first coined the term "Syndrome X" which later became "metabolic syndrome", published an article recently: The Metabolic Syndrome: Requiescat in Pace . \

Professor Edwin A M Gale of even more recently wrote Should we dump the metabolic syndrome?: Yes. He says, "Diagnosis of the metabolic syndrome is redundant in those who already have diabetes and adds nothing to the management of those who do not. "

He continues, "This is not a turf war: the confrontation reflects genuine perplexity within the diabetes community. One party maintains that a working definition is needed to resolve existing confusion; the other party argues that an inadequate definition merely adds to it. "

Dr. Gale alleges the use of "metabolic syndrome" is outdated and outperformed by other scoring systems which treat "continuous variables as continuous, whereas the metabolic syndrome treats them as dichotomous." He emphatically says, "the metabolic syndrome is a handy clinical label that lacks a useful definition."

Assuming the aforementioned "metabolic syndrome" is not declared dead, what is its value? Is it merely a set of symptoms which are part of a bigger whole or not actually related at all?

In Is the "Metabolic Syndrome" a Mild Form of Cushing's Syndrome? The Curious Story of 11beta-Hydroxysteroid Dehydrogenase, Dr. Ashok Balasubramanyam explores the role of 11beta-HSD (types 1 and 2). (There is a lot of current research ongoing with 11beta-HSD, easily found by using the term in PubMed and other medical search engines.)

Dr. Balasubramanyam elaborates:

One intriguing question is: Could a single primary defect trigger a cascade of diverse events leading to these apparently disparate metabolic, cardiovascular, and reproductive defects? Since Cushing's syndrome also encompasses many of these disorders, it is worthwhile considering whether the metabolic syndrome could be a "forme fruste" of Cushing's.

In Glucocorticoids, metabolism and metabolic diseases (full text version), the author states:

Indeed, hyperactivity of the HPA axis is positively correlated with the metabolic
syndrome as demonstrated in subjects with glucose intolerance, hypertension, and
insulin resistance (Reynolds et al., 2001a,b; Phillips et al., 1998; Phillips et al.,2000; Walker et al., 1998), suggesting a causative role for [glucocorticosteriods] in the obese phenotype...Taken together, increased GC levels or sensitivity in muscle have been associated with conditions related to the metabolic syndrome in several studies and models.

In Cortisol--cause and cure for metabolic syndrome? (full text version), the author makes the case for the similarity of metabolic syndrome and Cushing's syndrome.

Similarities between the metabolic syndrome and Cushing's syndrome, and reversibility of the features of Cushing's syndrome, suggest that cortisol may contribute to the pathophysiology of both conditions and that reducing cortisol action may provide a novel therapeutic approach in the metabolic syndrome...

...We have collected evidence that the HPA axis is ‘activated’in the metabolic syndrome. In cohort studies, we have shown that 09.00 h plasma cortisol after overnight fasting is elevated in subjects with relative glucose intolerance, hypertension, insulin resistance and hypertriglyceridaemia (Fig. 1) [2–6].This elevation of plasma cortisol in metabolic syndrome associates with increased cortisol response to low-dose (1μg)ACTH1−24, consistent with adrenal hypertrophy [7]. Integrated cortisol secretion, measured using mass spectrometry to assess total urinary cortisol metabolite excretion, is variably increased in subjects with the metabolic syndrome.

I have much, much more information, but shall save it for another post later this week. I hope to tie in information about PCOS, also.

Radiosurgery and increased mortality: Is there a connection?

This study takes a brief look at radiosurgery and its possible link to increased mortality. It does not distinguish between single-fractionated radiotherapy such as gamma knife and fractionated stereotactic radiotherapy (FSR).

The authors explore four (4) major areas:

• Cerebrovascular disease following pituitary radiotherapy
• Cerebrovascular mortality following pituitary radiotherapy for non-functioning adenomas
• Impact of pituitary radiotherapy on mortality in acromegaly
• Hypopituitarism and excess mortality following pituitary radiotherapy

I am mainly interested in the first and the last in the list above. These impact those with Cushing's who are considering or have undergone radiotherapy.

Cerebrovascular disease is already a risk with Cushing's patients. In Mortality in Patients Treated for Cushing’s Disease Is Increased, Compared with Patients Treated for Nonfunctioning Pituitary Macroadenoma (Dekkers, et al), the authors conclude:

[M]ortality is increased in patients with Cushing’s disease, compared with both NFMA and acromegaly. This implicates that transient exposure to cortisol excess is a major contributor of the increased mortality, even after cure of Cushing’s disease. This observation may also be of relevance for patients treated with exogenous glucocorticoids for nonendocrine diseases.

Cited in the same study, "Causes of death were cardiovascular disease in 23.4%, cerebrovascular disease in 12.8%, malignancy in 19.1%, and infectious diseases in 17% of all patients. " Thus, there is already a link to mortality due to cerebrovascular disease and Cushing's.

The Ayuk/Stewart analysis cited a "study of 331 patients with pituitary adenomas treated with surgery and radiotherapy [where] increasing doses of radiotherapy were associated with increasing risk of cerebral infarction." They go on to admit there is a lot of debate about what caused the cerebrovascular events, with radiation thought to be a cause due to "changes to the cerebral vasculature".

The Dekkers study counters that: "By regression analysis, in a model adjusted for age and gender, radiotherapy and hypopituitarism were not associated with increased mortality risk."

Ayuk and Stewart, when analyzing the data from multiple sources, disagree. Hypopituitarism is common after treatement for pituitary adenomas. They cite several studies which show "over 50% of patients treated with pituitary radiotherapy will develop deficiencies in one or more anterior pituitary hormones over the following decade." They then analyzed numerous studies which "examined mortality in patients with hypopituitarism and which found increased mortality compared with age-matched controls, predominantly due to cerebrovascular and cardiovascular disease."

In two of the studies analyzed, radiotherapy did not seem to attribute to increased mortality. But in another, larger study of over 1000 patients, "treatment with radiotherapy was associated with a significantly increased mortality rate" when comparing patients who had hypopituitarism from radiotherapy with patients who had hypopituitarism from other treatments or due to tumor.

Age may play a part, also:

The authors also reported higher mortality in patients who had been diagnosed at a younger age, with a standardized mortality ratio of 4.87 in the group younger than 20 years, decreasing to 1.0 in those older than 60 years. This is of particular relevance as over half of the radiotherapy-treated patients were younger than 50 years at the time of treatment.

Overall, the data is unclear about the link between radiotherapy and mortality. The authors were also unclear about whether the hypopituitarism was treated with hormone replacements and what significance this may have. I suspect this was partially due to the information available to them from the studies they analyzed.

John Ayuk, Paul M. Stewart (2008). Mortality following pituitary radiotherapy Pituitary, 12 (1), 35-39 DOI: 10.1007/s11102-007-0083-1

Hypopituitarism and Gamma Knife Radiotherapy

Does radiotherapy cause hypotituitarism when treating pituitary adenoma(s)?

Sometimes tumors cause damage to the pituitary gland which results in hypopituitarism and panhypopitituarism. Surgery to remove the tumor(s) can also cause damage to the pituitary which leads to hypopitutiarism. Sometimes, depending on tumor placement and the amount of pituitary removed, the pituitary regains total function. Nothing is cut-and-dry with this due to the numerous factors surrounding tumors and their removal.

This article takes a look at the effect of radiotherapy on the pituitary. Is hypopituitarism a "given" with radiotherapy or can it be avoided? According to the authors, this depends on the total dose, the fraction size of each irradiation, and the time between each fraction.

Since Gamma Knife is a single-fraction radiosurgery, all radiation is delivered in one dose.

Radiation-induced hypopituitarism occurs in a significant number of patients treated for pituitary adenomas with either stereotactic radiosurgery (SRS), which involves a single dose of stereotactic radiotherapy, as well as following fractionated stereotactic radiotherapy (FSRT).

The authors point out the risk is difficult to establish due to the multiple factors involved, which include:

• surgery
• variations in dosages of radiation
• technique used (SFR vs. FSRT)
• accuracy of placement and imaging
• pre-existing hypopituitarism
• lack of consisten protocol for diagnosing hypopituitarism

They also point out hypopituitarism is "more likely to occur following stereotactic irradiation for
secretory adenomas, as higher doses are generally required to achieve hormonal control." This includes gamma knife.

Since hypopitituarism can include multiple hormones, which are the most apt to be affected? Growth hormone (GH) has the greatest vulnerability. "With higher radiation doses (30–50 Gy), however,the frequency of GH insufficiency substantially increases and can be as high as 50–100%."

Patients irradiated for pituitary tumors have an increased risk for gonadotrophin deficiency with the data presenting "severity from subtle subclinical) abnormalities in secretion detected only by
GnRH testing to severe impairment associated with diminished circulating sex hormone levels."

Normal ACTH deficiency "dramatically increases (27–35%) after intensive irradiation [6, 9, 12] and more so (31–60%) in patients with pituitary adenomas [20, 25, 26]." TSH deficiency follows almost identically with patients irradiated for pituitary tumors.

Women tend to develop hyperprolactemia after SRS/GK which tends to normalize over time. The article was not very clear on this and just briefly touched on it. There didn't seem to be much data on it, either.

More on GK later this week.

Ken H. Darzy, Stephen M. Shalet (2008). Hypopituitarism following radiotherapy Pituitary, 12 (1), 40-50 DOI: 10.1007/s11102-008-0088-4

Gamma Knife Radiosurgery...

...A safe alternative for treatment of ACTH-producing pituitary adenomas?

For the next few posts, I'm going to examine the latest research about the use of Gamma Knife (GK) radiosurgery in the treatment of pituitary adenomas, especially ACTH-producing adenomas.

Although GK is called radiosurgery, there is no cutting involved. 201 "beams" of cobalt-60 gamma radiation are focused on the region to be treated. The beams go through the skull in different spots, with each beam too weak to hurt normal tissue. However, when they all come together in the area to be treated, they are then strong enough to destroy the tumor. It is a type of single-fraction radiosurgery.

Another method often used is fractionated stereotactic radiotherapy. The Johns Hopkins' site explains FSR this way:

[With FSR] multiple fractionated doses or fractionated stereotactic radiation can be delivered. The main advantage of fractionation is that it allows higher doses to be delivered to the tumor because of increased tolerance of the surrounding normal tissues to these smaller fractionated doses. In other words, while single-dose stereotactic radiation takes advantage of differences in the pattern of radiation given, fractionated stereotactic radiation takes advantage of not only the pattern, but more importantly of the differing radiosensitivities of normal and surrounding tissues. Another advantage is so-called ”iterative” treatment, meaning the shape and intensity of the treatment plan can be modified during the course of therapy.

Dr. Molitch and Professor Grossman¹, in the March 2009 issue of Pituitary which focuses on radiotherapy for pituitary tumors, introduce the issue as guest editors. In their introduction, they say:

As of yet, there are no adequate studies to conclude whether there is one mode of single-dose radiotherapy that has superior efficacy or safety, and indeed direct comparisons of single-dose vs. fractionated stereotactic radiotherapy (FSR) are all but non-existent.

GK radiosurgery is done in one session. FSR takes multiple sessions spread over a period of time. The head must be in the exact position during each session. For many reasons, including ease, GK has become the preferred method.

In the same issue of Pituitary, Dr. Mary Vance at the University of Virginia² discusses the use of radiation therapy in the treatment of Cushing's disease. According to Dr. Vance, radiation therapy is used "most commonly as adjunctive therapy after unsuccessful pituitary surgery."

Dr. Vance reiterates the fact that GK is "not suitable for a large lesion close to the optic nerves or optic chiasm" and that all radiation therapies do cause loss of pituitary function eventually. She also emphasizes "There are no prospective studies comparing the results among different methods of radiation delivery regarding efficacy, development of new pituitary hormone deficiency or complications."

Points that Dr. Vance makes about any type of radiation therapy:

• Basically used when transsphenoidal surgery doesn't work
• Takes time (months to years) before it works
• Medical therapy (ketoconazole or metyrapone) to lower cortisol may be needed in conjunction with radiation treatment until it works
• Patient needs to be monitored closely for liver problems due to drug therapy and for lower natural production of cortisol

Dr. Vance has a nice summary of the various types of radiation therapy which include gamma knife (GK).

The Gamma knife series of 90 patients treated at the University
of Virginia found that a normal 24 h UFC level occurred in 49 patients (54%) at an average time of 13 months (range 2–67 months). Ten patients (20%) had relapse of Cushing’s with the mean time to relapse of 27 months (range 6–60 months). Seven of these patients underwent a second Gamma knife treatment, three achieved remission. Five of the seven patients (71%) who had a second Gamma knife treatment developed a new visual or 3rd, 4th or 6th cranial nerve deficit. These cranial nerve deficits either resolved (two patients), improved (two patients) or persist(one patient) (New pituitary hormone deficiency developed in 20 patients (22%)

This research also indicates there is no known safe radiation value for second attempts with GK.

The development of cranial nerve deficits and visual loss after a second Gamma knife treatment, in this study and in an another report [14], suggests that the presumed safe radiation dose to the cavernous sinus and optic chiasm and optic nerves is not known. For this reason, and until more definitive information is obtained, a second Gamma knife treatment should probably be avoided.

Dr. Vance points out that although radiation therapy is not perfect, there really is no perfect treatment for Cushing's disease at this time.

More posts on GK as a treatment coming this week.



1. Mark E. Molitch, Ashley B. Grossman (2008). Pituitary radiotherapy Pituitary, 12 (1), 1-2 DOI: 10.1007/s11102-008-0148-9

2. Mary Lee Vance (2008). Cushing’s disease: radiation therapy Pituitary, 12 (1), 11-14 DOI: 10.1007/s11102-008-0117-3