NEW YORK Dr. Whitney A. High is into heavy metal and skin, but if you think he's a biker with a leather vest and a Black Sabbath tattoo, you've got it wrong.
Dr. High, of the University of Colorado, Denver, is a clean-cut young dermatopathologist with a soft spot for geology and physics, and his interests in heavy metal involve titanium and vanadium, not Metallica and Megadeath.
His unique set of interestsskin disease, metals, and physicshas landed him in the center of the growing controversy around gadolinium contrast agents and their role in nephrogenic systemic fibrosis.
Dr. High is part of an elite team of investigators trying to determine whether the gadolinium agents in MRI contrast media play a causative role in this devastating, largely untreatable skin disorder. Their answer could have major medicolegal and clinical implications.
Nephrogenic systemic fibrosis (NSF) is characterized by excessive fibrosis in the skin and other soft tissues that leads to disfigurement, tissue constriction, and in some cases, respiratory failure, ocular damage, and cardiac problems. It was first reported as "scleromyxedema-like disease" in renal dialysis patients in 1997. In the last decade, hundreds of cases have emerged worldwide, primarily, if not exclusively in people with end-stage renal disease (ESRD). Other than that, there were few clues as to what caused the distinctive skin and soft tissue changes.
"For a long time, we could not figure out what was going on," Dr. High said at the American Academy of Dermatology's Summer Academy 2007. The first break came in January 2006, when Austrian researchers described nine patients with ESRD, five of whom had developed NSF, with all five having undergone imaging procedures with gadolinium contrast agents. These five patients developed signs and symptoms consistent with the disorder within about 4 weeks of exposure to gadolinium-based contrast used in magnetic angiography.
Further damning evidence emerged late last summer, when Danish investigators reported that 13 of 13 ESRD patients with NSF had received gadodiamide, a commonly used gadolinium contrast agent. There were no other shared risk factors among the 13 cases.
Is there a gadolinium smoking gun in the tissues of NSF patients? That's the question Dr. High is seeking to answer.
"I had previously reported on a granulomatous reaction to titanium alloy in a patient with ear piercings. That's how people knew I was interested in metals and skin disorders, and that's why I got called in on this gadolinium issue," he said.
There are five gadolinium contrast agents currently in use around the world. The two most common are Magnevist (gadopentetate) and Omniscan (gadodiamide). Manufacturers of the products, already reeling from the Food and Drug Administration's recent issuance of a black box warning about the potential risk of NSF, are hoping that gadolinium will be judged an innocent victim of circumstance.
Malpractice lawyers, of course, hope for the opposite.
So far, the findings seem to be favoring the lawyers. Using a technique called energy dispersive spectroscopy (EDS), investigators are able to detect metals such as titanium, vanadium, and gadolinium in human tissues, said Dr. High. He has detected gadolinium in the skin of four of seven NSF patients he has studied (J. Am. Acad. Dermatol. 2007;56:21-6).
He stressed, however, that EDS is "a semiquantitative technique, not a mass-based technique, and it should not be used as such." EDS can tell whether certain metals are present in the tissue, but it cannot be used to determine how much is present, except in a relative type of way.
That type of determination requires a technique like mass spectrometry. This method, too, showed significantly elevated levels of gadolinium in all NSF patients of Dr. High's original series.
Dr. High and his colleagues have used mass spectrometry to analyze a range of different tissues. Infant foreskin samples, predictably, show no gadolinium. Multiple sclerosis patients without renal problems who had undergone semiannual MRIs showed no gadolinium. Tissue samples from Mohs surgery for skin cancer? Also clear, as were skin samples from ESRD patients who have not had gadolinium-based scans. ESRD patients who had undergone imaging with gadolinium contrast, however, did show traces of the metal albeit at much lower levels than the patients with NSF.
Circumstantial? Unlikely. "If you have gadolinium in your tissues, you got it from somewhere. There is no regularly encountered source of gadolinium in this form in nature. So unless you happen to be a gadolinium miner, you got it from a doctor," said Dr. High.
But Dr. High seems reluctant to pin blame for NSF exclusively on gadolinium contrast agents. Bear in mind that nearly all NSF patients have ESRD, meaning that their ability to filter and eliminate toxins such as metals is sorely impaired. "Renal failure patients are a toxic soup of metalscalcium, iron, zinc, copper, aluminumall sorts of metals," Dr. High said, adding that he believes NSF results from "a collusion of coconspirators. Gadolinium alone may not be the only prerequisite exposure, and other metals may be involved in its deposition or in disease evolution." Only time will tell.