Sunday, March 8, 2009

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.

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)

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

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.

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.

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

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

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

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.

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

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.

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. :)

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

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

03:27 PM Mar 06, 2009
@doc_rob @ARUPlabs has great site for tests.

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

03:27 PM Mar 06, 2009
@doc_rob @ARUPlabs has great site for tests.

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

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

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?

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

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.

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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.


  1. Let me respond.

    Metabolic syndrome is, by definition, an array of symptoms and clinical findings. It is called a syndrome because there is not clarity that there is a single disease process at work (as some of your sources stated). I won't argue that point, although there is very compelling reasons to think hyperinsulinism plays a major if not central role. I agree that this is often regarded as a disease, and not a syndrome, but from a practical standpoint it doesn't matter much to me.

    Why? The purpose of identification of the syndrome is to risk-stratify a person. What really matters to me is mortality and morbidity. I treat things or test for things because they either make someone die early or cause significant harm. In this way, the term "Metabolic Syndrome"is useful. People with MS are at significantly increased risk of developing diabetes and coronary artery disease. It is very useful to identify people at risk for these serious diseases.

    Besides - it sometimes scares people into changing their lifestyles enough to lose weight and eat better. In that way, it is very useful.

    Regarding the correlation between the pituitary/adrenal axis (cushings) and MS, I think your evidence is interesting, but circumstantial. The fact that people with MS have an abnormal HPA axis doesn't prove cause. From what I see, it is equally likely that MS is the cause of this abnormality of the adrenocortical system, not the reverse.

    The fact the two things look alike can be explained by the fact that increased cortisol levels cause insulin resistance, resulting in hyperinsulinism - which in turn makes the person look to have MS.

    There probably are some MS patients who are actually low-level cushings. To say that all MS is from this cause (or even most) is really pushing your data. To prove this, one would have to reverse the process of MS by using an adreocortical antagonist - fixing the hypercortisol state and having it followed by a remission of MS. By my reading, your data didn't show this.

    The bottom line for me, however, is the "so what" question. I am only marginally interested in the root causes if they don't impact my treatment or diagnosis. Aggressive risk factor reduction and lifestyle modification are the approaches in a patient in MS. The cortisol balance doesn't come into play.

    Let me say, however, that the 18 year old is different. He has all sorts of red flags, as he is very unusual in his presentation. The incidence of MS in teens, although rising, is not high and so other causes must be considered - especially as his onset was somewhat rapid.

    Bottom line? Maybe there is an association, but I am not convinced that it is a causal association. But how does it impact me? Not much, except that I need to keep vigilant and not assume all MS patients are the same. I need to keep my eyes open for Cushings -which I have much more since I have been interacting with your community. I have tested much more for it, and I thank you for the reminders.

  2. Thanks for the comment/response, Dr. Rob. I think this kind of conversation is awesome, and appreciate the fact you not only allowed it on twitter but also will continue it here. I do have more information. My goal is not to tell you or anyone else what to think. My goal is to get people to see RECENT/CURRENT information.

    We all win when the best interest of the patient is served. Thank you.

  3. Robin, don't you know by now? It is NEVER Cushing's, unless you are a dog. Even when it is Cushing's, and the tumor comes out and slaps the doctor and the pathologist across the face, it still isn't Cushing's. It is NEVER Cushing's. Only horses and dogs and ferrets get Cushing's. I should know, I looked it up on Google. ;)~



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