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.

When cortisol is a night owl....

....or all about diurnal rhythm.

What ARE you talking about, Robin? I can hear it now. Yes, we hear a lot about cortisol and how lowering it by lowering stress can affect our weight. I'm sure you've seen the ads for the cortisol-slimming drugs/herbs, too. And we are talking about the same hormone. What is cortisol, anyway?

Cortisol is a corticosteroid hormone produced by the adrenal cortex, the outer layer of the adrenal glands which are essentially lying on top of the kidneys. Without it we die. It is the hormone that responds to "stress", both good and bad. It affects levels of multiple other hormones and electrolytes, which is another topic for another day. However, the short of it is, it is very important in the homeostasis of the body.

When the body is functioning normally, cortisol is regulated by the pituitary in a negative feedback loop with ACTH (adrenocorticotropic hormone). Basically, the pituitary produces ACTH when the body's cortisol level is low, which stimulates the adrenals to produce cortisol. ACTH is pulsatile, which means it is produced in spurts instead of evenly or consistently.

What does all this have to do with cortisol being a night owl?

In a "normal" person, cortisol is the highest around 8 a.m. and decreases to about half that value around 4 p.m. By midnight (give or take an hour each way), cortisol should be about zero or close to it with blood and salivary levels. This is a normal diurnal variation. It is also called the circadian rhythm.

When one has Cushing's, this circadian rhythm is lost, and the normal diurnal variation changes. Cushing's patients have "flat" diurnal levels of cortisol, or even higher levels at night instead of in the morning.Endotext.com explains it really well. Their diagram shows the difference between normal serum cortisol levels and the levels for those who have Cushing's. (Click on the link or the picture to see it better.)

Where does that take us? Well, to testing. Because of this change from normal to warped diurnal rhythm (or lack of), testing cortisol levels can be very useful when diagnosing Cushing's Syndrome/Disease.

The article, "Cushing's Syndrome" by John Newell-Price, Xavier Bertagna, Ashley B Grossman, Lynnette K Nieman, Lancet 2006; 367: 1605–17,Division of Clinical Sciences, University of Sheffi eld, Northern General Hospital, Sheffi eld, UK (J Newell-Price FRCP); says:

Midnight plasma cortisol or late-night salivary cortisol: Normal circadian rhythm of cortisol secretion is lost in patients with Cushing’s syndrome. A single sleeping midnight plasma cortisol concentration of less than 50 nmol/L effectively excludes Cushing’s syndrome at the time of the test and this might be especially helpful in patients in whom there has been incomplete suppression on dexamethasone testing. Concentrations of more than 50 nmol/L are noted in individuals with Cushing’s syndrome, even those who suppress serum cortisol on low-dose dexamethasone testing,96 but this cutoff lacks specificity because patients with acute illness also have values above this concentration. An awake midnight concentration of cortisol in plasma of more than 207 nmol/L diff erentiates between Cushing’s syndrome and other causes of hypercortisolaemia but can miss mild disease diagnosis in about 7% of cases. (The conversion factor of ug/dL x 27.6 = nmol/L)

So, being a night owl doesn't make you "Cushie", but if you are Cushie, you probably are a night owl. Of course, that brings us to yet another topic for another day....cyclical/intermittent/episodic Cushing's.

Cortisol whoooooooooooooooooooooooooooo.........???

A horse of a different color

Or should I say zebra? In med school, potential doctors are told ""When you hear hoofbeats, think horses, not zebras". Well, what about those of us who are zebras? What does that say to those who don't fit any mold of illness or have multiple illnesses which paint stripes?

As I said earlier, my primary care doctor sees horses, but every now and then she does notice a stripe. The thing is, she tries to get rid of the stripe instead of looking at what caused it. And she's not alone. Frankly, I'm wondering if there really are any horses out there? Ok...ok....I guess there are. Maybe.

Diabetes, you say, is a horse. Nope.... Did you know that endocrine disease can cause it? And that it is just a secondary symptom? You didn't know that? Don't worry. Most endocrinologists don't seem to, either. Thankfully, I never had that particular stripe.

Ok, how about thyroid function/disease? Nope, not that one either. It's actually a stripe in the zebra of endocrine disease, especially a pituitary tumor. Secondary/central hypothyroidism is linked to a pituitary tumor suppressing the pituitary, and hyperthyroidism can be linked to a TSH producing tumor.

Low hormones? Oh, that must be early menopause or pre-menopause with females, right? Wrong. Just stripes of another color in the zebra of pituitary tumors.

How about high hormones? Well, guess what? Do I need to say it? More stripes...... Pituitary adenomas are famous for growth hormone and ACTH overproduction.

PCOS and metabolic syndrome are often the horses with which a Cushing's patient is diagnosed. Too often, it's just too easy to camouflage the stripes with those diagnoses.

Oh, and my favorite. Obesity. "You need to eat less and get more exercise." How many people do you know who want to be extremely overweight? Those doctors who don't listen, ignore the stripes (some literal ones called striae) and keep repeating that mantra need a A Swift Kick in the ASP. They don't know that fat is an endocrine organ. They also don't know it is actually possible to literally starve while remaining obese.

I do not know the answers. I do know there is a problem. Instead of heading to the dude ranch, maybe med schools ought to take their future doctors on a safari.