February 2010
Feature Story

Karen Titus

The medical world may not be eager to embrace another syndrome. But perhaps it is ready to accept a less stringent, though still inclusive, way to think about a gang of risk factors that, like certain low­lifes, often hang out together and, likewise, are up to no good.

The no-goodniks are, in this case, raised blood pressure, elevated triglycerides, lowered high-density lipoprotein cholesterol, raised fasting glucose, and obesity (particularly central adiposity)—interrelated risk factors for diabetes and cardiovascular disease.

That list does not trip lightly off the tongue. Handier to lump them together as “metabolic syndrome,” a term physicians commonly use when multiple such risk factors are present.

They might be less comfortable defining this clinically. Though physicians have long known about the affiliations between these risk factors, there’s been little agreement of terminology and diagnostic criteria, including whether metabolic syndrome should be used as a diagnostic term. Perhaps these risk factors are merely unrelated phenotypes. A point-counterpoint debate took place in the pages of Clinical Chemistry several years ago (2005;51: 931–938), with none other than Gerald M. Reaven, MD, arguing that the criteria should not be considered a diagnostic entity. The title of his paper? “The metabolic syndrome: requiescat in pace” (may it rest in peace). It was Dr. Reaven who first drew major attention to the notion of metabolic syndrome (then termed syndrome X) more than 20 years ago with his Banting Lecture (Diabetes. 1988;37: 1595–1607), when he suggested that central obesity, diabetes, and hypertension are driven by insulin resistance and impaired glucose tolerance.

The irony of his renunciation (if that’s not too strong a word) was not lost on many in the laboratory community. It was as if a Founding Father had decided to roll up the Constitution and start agitating for a monarchy. Dr. Reaven has not been alone in suggesting there’s no need to coin this a syndrome. Some say patients with the risk factors will be treated regardless; others, sticklers for precision, say the risk factors do not meet the strict criteria for a medical syndrome.

The discussion will not be resolved in the pages of CAP TODAY. But the time might be ripe to usher in a Pax Metabolica, if you will, and look at metabolic syndrome through the eyes of laboratory professionals.

William E. Winter, MD, notes that seven major groups have offered definitions of metabolic syndrome over the past 10 years. All the groups include raised fasting glucose, raised triglycerides, lowered high-density lipoprotein, and raised blood pressure measurements, observes Dr. Winter, professor, Department of Pathology, Immunology, and Laboratory Medicine, and professor, Department of Pediatrics, University of Florida College of Medicine, Gainesville. Most, but not all, groups include waist circumference, body mass index, or both; two include insulin resistance, microalbuminuria, or both. Despite a fair amount of overlapping criteria, not all agree that “metabolic syndrome” is a diagnostic term.

The latest attempt to get everyone sailing in the same direction is a joint interim statement, published last October in Circulation (Alberti KGMM, et al. 2009;120:1640–1645), courtesy of six groups, including the International Diabetes Federation Task Force on Epidemiology and Prevention; the National Heart, Lung, and Blood Institute; and the American Heart Association. The groups looked at the chief difference among competing definitions—waist circumference. The upshot? Waist measurement need not be an obligatory component, the statement said, but would remain a useful preliminary screening tool.

One selling point of the recent statement, says Neil Harris, MD, also of the University of Florida, is, “It will make it a lot easier for laboratorians to comment about the metabolic syndrome.”

The criteria reinforced in the joint statement are, apart from that poke in the belly, quite amenable to fairly routine lab analysis, says Dr. Harris, medical director, core laboratory, Department of Pathology, Immunology, and Laboratory Medicine, and clinical associate professor.

Just as important, Dr. Harris says, the joint statement reflects a “reasonable consensus,” one that laboratory professionals should feel comfortable using and sharing with their clinical colleagues. “It’s a useful summary,” he says. And it’s a good reminder, he adds, that (as the statement notes) patients with metabolic syndrome are at twice the risk of developing cardiovascular disease in the next five to 10 years as those without the syndrome and have a fivefold increase in their risk of type 2 diabetes.

Daniel M. Hoefner, PhD, MT, clinical chemist, Marshfield (Wis.) Labs, agrees the joint interim statement will add more oomph to discussions. A lack of consensus regarding diagnostic criteria has “been a major stumbling block,” he says, along with the debate over whether the cluster of risk factors deserves to be crowned a syndrome.

As helpful as the new statement might be, note the use of the word “interim.” The stream of organizations issuing new or revised criteria seems endless, which has made it hard to pin matters down, says Ross J. Molinaro, PhD, MLS(ASCP), assistant professor, pathology and lab medicine, and medical director, core laboratories, Emory University Hospital Midtown, Atlanta. He views the joint statement by Alberti and others to be a first step toward standardizing the criteria used to diagnose metabolic syndrome and says there’s now a need for evidence of the downstream clinical benefits of, or patient outcomes associated with, using the criteria. “The focus will now likely be on the remaining professional groups to join the effort and come to a consensus on waist circumference thresholds in different populations using clinical outcome studies,” he says.

It’s all very Kafkaesque: relying on an “interim statement” about a syndrome that often appears between air quotes.

In practice, the various elements of the metabolic syndrome are scattered, and remind one not so much of a syndrome as a bureaucracy. Who’s responsible here? Who has all the information? Can the pieces be pulled together somehow, or must we really visit (one imagines exasperated patients saying) five different departments to identify, let alone fix, this problem?

While bureaucratic problems often breed even more bureaucracy, there may be a relatively simple answer here. Someone needs to heed these risk factors and know they might be acting in concert. That someone could well be the laboratory.

Dr. Hoefner falls in the prosyndrome camp for reasons that are practical, not ideological. Like many lab professionals, his worldview easily sees shades of gray, which often sets him apart from the black-and-white world of many clinicians. “They rely on strict cut points,” says Dr. Hoefner. “They want to know, is it elevated?”

Dr. Hoefner provides an example of what for him is a gray area: a 40-year-old sedentary male with a few worrisome, though not alarming, characteristics, including slightly elevated triglycerides (160 mg/dL) and slightly low HDL (38 mg/dL), both of which meet the diagnostic criteria for metabolic syndrome. Fasting glucose is 98 mg/dL, which does not. The patient is mildly hypertensive (completing the diagnosis) and slightly overweight.

Considering this hypothetical but not-hard-to-imagine patient, Dr. Hoefner says viewing the risk factors through the lens of the metabolic syndrome would be helpful. “It triggers a clinician to say, ‘Individually those values may not be that bad, but taken together we need to be a little more aggressive with some type of treatment.’”

Left unchecked, the risk factors can have severe consequences, says Dr. Winter. Regardless of how metabolic syndrome is defined, he says, “most people would say that a patient with a metabolic syndrome has a problem with insulin sensitivity,” which can be manifest in numerous ways.

Dr. Winter says one way to characterize the consequences of insulin resistance would be to ask, what are the consequences of an absolute elevation in insulin concentration, where the beta cell is trying to respond by overproducing insulin? Epidemiological studies show a relationship between atherosclerosis and hyperinsulinism, possibly related to insulin’s potentially being a growth factor. “We know that it is a very important growth factor in utero. It may be a growth factor for atherosclerosis,” says Dr. Winter, “although whether it’s a direct cause of atherosclerosis, or only through an effect of other atherogenic factors, is controversial. But certainly people who have insulin resistance, who have high insulins, have endothelial resistance. They can often have hypertension.” Hyperinsulinism might also change the sympathetic nervous system, he says, resulting in more vasoconstriction.

Hyperinsulinism has been shown to stimulate plasminogen activator inhibitor-1, which is a prothrombotic factor. “We know that people who are hypercoagulable, relatively speaking, have more problems with atherosclerosis,” Dr. Winter says.

Hyperinsulinism is also associated with women having higher androgen levels, and subsequent problems with irregular menses, amenorrhea, or even frank infertility. Acanthosis nigricans is thought to be a consequence of hyperinsulinism as well.

Hyperuricemia is not uncommon in patients with the metabolic syndrome. “And there’s some data to suggest that hyperuricemia may be involved with atherogenesis,” Dr. Winter says.

In the metabolic syndrome, he says, despite the fact that the beta cell attempts to compensate for insulin resistance, patients can still have inadequate insulinization. “So, you’ve not overcome all the metabolic problems. Patients can have either abnormalities of glucose or abnormalities of lipids.”

Even if patients are not hyperglycemic, being hyperinsulinemic appears to produce a pro-inflammatory state, he says. This is hardly new ground—the relationship between inflammation and atherosclerosis is well known. But in addition to dyslipidemia—high triglycerides, low HDL—being atherogenic, it independently has been associated with non-alcoholic fatty liver disease, Dr. Winter says, which is a common cause of cryptogenic cirrhosis. “Non-alcoholic fatty liver would be only the tip of the iceberg,” he says, noting it could progress from fatty infiltration of the liver to an inflammatory infiltrate into the liver and, ultimately, to fibrosis of the liver, leading to cirrhosis and later hepatoma or liver failure.

Patients who are obese—especially if they have centripetal obesity—have elevated free fatty acid levels in their blood, says Dr. Winter. This is not a routine diagnostic measurement, but it does provide insight into the mechanism of insulin resistance. Fatty acids provide twice as much energy as glucose, he says; tissues will preferentially burn the former over the latter, which means glucose won’t be cleared. That can contribute to glucose elevation. “We know that when you have elevated triglycerides, you can get, as part of the metabolic syndrome, fat distribution not only in the liver (causing non-alcoholic fatty liver), but also fat deposition in, for example, the muscles.” Fat distribution in skeletal muscles can contribute to insulin resistance. It turns out, says Dr. Winter, that fat appears to produce tumor necrosis factor alpha, which can produce tissue insulin resistance.

Dr. Molinaro offers his own simple suggestion for gauging the spread of metabolic syndrome, starting with the risk factor of abdominal obesity. “Take a walk and look around.”

Clinicians can see if a patient is overweight; they know the patient’s blood pressure. And they’re the ones who can start with the most basic (if not always easy-to-follow) strategies—helping patients lose weight through diet and exercise.

Lab professionals are not going to start gauging belly fat. But, as Dr. Molinaro notes, physicians can’t make a diagnosis of metabolic syndrome without a laboratory test, whether it be glucose, triglycerides, or HDL.

So who should take the lead?

Given the vague nature of metabolic syndrome, Dr. Harris’ suggestion is fitting. “This is definitely perhaps a potential area where labs can possibly play a bigger role,” he says. Definitely. Perhaps. Potential exists—possibly.

Metabolic syndrome doesn’t have its own panel. “On the other hand, I would argue that it’s routine care for adults to assess their lipids and their glucose,” says Dr. Winter. It may not need to be much more complicated than that, he says. And they can remind clinicians that patients who have central obesity are at risk for having type 2 diabetes and at risk for dyslipidemia, Dr. Winter says.

Nor does he see much need for labs to develop even more tests, although several have been suggested, including oxidized LDL. Dr. Molinaro agrees, noting that the more esoteric tests are only in their infancy.

Dr. Winter is familiar with all the myriad other tests out there, and their possible role in diagnosing the metabolic syndrome. He can discuss them, and does, in great detail. And then he returns to his basic premise: Why make this harder (or more expensive) than it needs to be? “You can get a lot of basic information by taking the patient’s blood pressure, measuring their height and weight and calculating their BMI, measuring their abdominal circumference, knowing what their fasting plasma glucose is, and maybe, in the future, their A1c.”

Dr. Hoefner wants to keep it simple, too. “The more tests you have, the more complex it gets. This is not something where we want a high degree of specificity. We’re trying to use this as a flag, to make clinicians aware that the problem of the whole is much more important than each individual component.”

Dr. Harris says there’s plenty for labs to do even with these basic tests. “If patients have a lipid profile performed, it’s well within the lab’s scope to have a pathologist look at the profile and provide a consult or comment that directs the clinician.”

He even floats a more edgy approach. “In some cases—as long as it’s been approved, and it’s in compliance with the hospital’s ordering policies—in an ideal situation the pathologist could actually order additional testing.” He admits this is controversial. “But as clinical pathologists—and I can speak for Dr. Winter—we’d like to see a bigger role for ourselves,” he says.

In his experience, clinicians tend to see the various elements as discrete items, rather than the whole picture. Pathologists, on the other hand, take in a wider view. It’s like traveling abroad—do you take the Grand Tour of Europe, or stick to Italy? Dr. Harris sees labs as advocates for the broader view. “We see the clinical history, and we see all the lab reports. And sometimes we can see things that are not immediately apparent to the clinical service.”

Seeing is one thing; action is another. Metabolic syndrome is a bit like a New Year’s resolution, and both cover similar ground: Eat right, exercise, trim that spare tire around the middle. You could do something about it. You should do something about it. And then ... you don’t.

Dr. Hoefner sounds like someone who’s about to turn this into a resolution, and perhaps start giving clinicians more guidance. “As a matter of fact, as we’ve been talking, I’ve been thinking to myself, I wonder if it’s worthwhile to have these discussions here at Marshfield.” The organization uses electronic medical records. “Maybe we can pull out a couple of these pieces and start flagging this,” he muses.

Dr. Harris is of the same semi-committed mind. “Pathologists are in a position to change the culture. We are trying to be more active in advising our clinicians, calling them and discussing cases with them,” he says.

And what else is he doing at Florida? “I have to confess—we’re not doing anything formal at the moment,” he says, sounding a bit rueful.