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Picking a path for PTH testing May 2002 Parathyroidectomy has an excellent success rate, with a 95 percent chance of curing a patient with hyperparathyroidism. But the operation as it is performed at many hospitals has an element of unpredictability: It may be complete, but a critical step remains before the anesthetized patient is ready to be awakened. The laboratory conducts a single test to determine whether all the diseased glands have been excised, or whether the surgeon needs to explore further. That test is an intraoperative assay of intact parathyroid hormone, or PTH, and it must be performed rapidly. In fact, the first commercially available rapid PTH assay was designed as a point-of-care test only about six years ago, and many hospitals, when they began performing rapid PTH assays, did them right in the operating suite. But in an unusual turnabout, despite the continuing availability of portable instruments, at a growing number of hospitals rapid PTH testing is migrating back to the central laboratory. The College’s Point-of-Care Testing Committee discovered the trend in a 2001 poll of 370 responding labs participating in the CAP Special Ligand Survey. "Initially, intraoperative PTH was meant to be an operating room assay," says committee junior member Alexis B. Carter, MD. "We were surprised to find that 71 percent of laboratories performed the test in a central laboratory, six percent in satellite laboratories, and only 23 percent in operating suites." It’s an interesting example, she says, of how the commercial availability of new assays can drive some tests back into the central laboratory. Intraoperative PTH testing is probably the most widely applied intraoperative hormone measurement, with two main manufacturers in the United States. Nichols Institute Diagnostics, which makes the Quick Intraoperative PTH assay, has contracts with 80 U.S. hospital laboratories, and Diagnostic Products Corp. has an approximately equal number of accounts for its Immulite Turbo Intact PTH assay. In the poll, about 20 percent of laboratories that reported doing rapid PTH used other methods such as the Roche Elecsys analyzer. Roughly three in 10,000 persons are affected by primary hyperparathyroidism. In the outpatient population, it’s one of the most common causes of hypercalcemia. "Stones, bones, and groans" is the medical-school mnemonic that summarizes the primary manifestations of hypercalcemia, which often leads to kidney stones, accelerated bone loss, and gastrointestinal discomfort. But only about 15 percent of patients with hypercalcemia have symptoms. For patients with hyperparathyroidism, the only definitive therapy is parathyroidectomy, a procedure that in the past has had a failure rate of up to five percent in experienced hands. It’s complex, because the locations of the four small parathyroid glands in the neck and mediastinum vary from patient to patient, and some patients have extra glands. "Typically, there are four," says Dr. Carter, who is a pathology resident with the Brody School of Medicine at East Carolina University in Greenville, NC. "However, three to as many as seven have been reported in a single patient." In addition, it is difficult to tell adenomas from hyperplasia either by surgical inspection or histologic examination. At least one standard surgical textbook, in fact, still advocates the traditional approach to parathyroid surgery: a bilateral neck dissection. In this procedure, Dr. Carter says, "surgeons make a neck incision, explore both sides, and attempt to identify all four of the parathyroid glands in their usual positions—in and around the thyroid gland. If any are enlarged, they resect and submit them for frozen section tissue confirmation." "In most cases a good surgical pathologist can identify whether the specimen is a parathyroid gland versus a lymph node or nodule of thyroid tissue," she continues. "But the single biggest problem with parathyroid surgery is the possibility of missing an ectopic hyperfunctioning parathyroid gland." Once researchers discovered that hyperfunctioning parathyroid glands took up a certain radioactive agent, physicians started doing preoperative localizing scans, called technetium-99m sestamibi scans, on these patients. "The idea was if you found only one enlarged gland by the scan, you wouldn’t have to do the bilateral procedure," Dr. Carter explains. "The reason that this is important is that whenever you operate in general, especially in the neck, the scar tissue formation can be quite intense. If for any reason someone has to go back in and re-operate, the scar tissue can obscure the anatomy and cause significant difficulties. The chances of surgical failure increase dramatically when operating for the second time, and there’s a much higher risk of complications." But the nuclear medicine scan isn’t perfect. Walter E. Pofahl, MD, an associate professor of surgery at the Brody School of Medicine, says the test’s sensitivity for a single adenoma is between 70 percent and 85 to 90 percent. That’s where the rapid PTH assay comes in. Says Dr. Carter, "If the surgeon removes the preoperatively localized gland and the patient’s PTH level drops dramatically, then the surgeon may feel comfortable that all of the diseased tissue has been removed. The remainder of the neck may be left untouched, which decreases patient complications." "If the scan shows a single gland," she says, "the surgeon takes the patient to the operating room and goes directly to that area." Before the surgeon performs the incision, he or she draws a baseline rapid PTH assay, exposes the gland, and removes it. "At that point the surgeon waits," Dr. Carter says. "At our institution it’s 10 minutes, but in the published literature it varies from five to 15 minutes. Then the surgeon draws another PTH level. If the second level has decreased from the baseline level by 50 percent, then this is indicative of complete removal of hyperfunctioning parathyroid tissue. The surgeon will close the patient and end the procedure." "If the PTH does not decrease by 50 percent, the surgeon may first send the resected gland for a frozen section to confirm that parathyroid tissue was indeed removed." Then, based on the results, he or she will start to explore for an undetected enlarged gland. Dr. Carter and Dr. Pofahl work at Pitt County Memorial Hospital, the tertiary care medical center for a 29-county area in eastern North Carolina, and surgeons there perform 30 to 50 parathyroidectomies per year. They use the Diagnostic Products Corp. assay, and the test is conducted only in the central laboratory. When Dr. Pofahl performs a parathyroidectomy, he removes the gland, then waits 10 minutes and draws a rapid PTH. "The DPC takes 14 minutes. The Nichols is a little quicker; once it’s in the laboratory it takes 10 minutes," he says. "During that period, the patient remains anesthetized," he continues. "We go ahead and close the incision, because at that point if the second PTH level falls below 50 percent of the baseline, or drops by half, then it shows we’ve taken out the right one. It’s not too often that you need to go back" and continue exploring. "I did one last week where the initial baseline was above 200 and the followup was less than 100, so the operation was completed." The assay is most helpful in allowing a minimally invasive parathyroidectomy, he says, but it’s occasionally used to document results of a bilateral neck procedure. "Occasionally before the operation the scan doesn’t show a single gland. In that instance, we go ahead and do a full neck exploration and find all four glands," Dr. Pofahl says. In his experience, it takes about an hour for a minimally invasive parathyroidectomy, and about 90 minutes for a whole-neck procedure. But he disagrees that there are many more complications with whole-neck. "You’re trying to improve on an operation with an exceptionally low complication rate and over a 95 to 98 percent cure rate," he says. "It’s tough to improve on, and intraoperative testing is more expensive. But if you can localize a single gland more quickly, you have obvious cost savings." Performing the test in the operating room has many advantages, Dr. Carter says. On the plus side, "you have more rapid turnaround time, so the surgeon can more quickly determine if he or she has to look for another enlarged gland, and it practically eliminates the need for specimen transport and errors associated with specimen accessioning in the central laboratory. The medical technologist also gets some good experience with direct patient care." Cost, however, is the downside. The pathology department at the University of Texas Southwestern Medical Center in Dallas reported that the cost of 50 parathyroid gland surgeries over a five-year period was $760 per surgery for intraoperative testing versus $360 for central laboratory testing.1 Dr. Carter views this as the best comparison on the subject because it includes the costs of operating time, laboratory overhead, instrument and reagent costs, technologist time, and other factors. Paul G. Catrou, MD, the head of clinical chemistry at Pitt County Memorial Hospital, says, "We saw the price [of the Nichols assay] back about two years ago. We just kind of shrugged our shoulders and said the hospital probably wouldn’t want to pay for it since it’s a lot cheaper to do it in the central lab using a multiple-assay device. So we brought in the Immulite Turbo test instead." That decision reflects a common pattern where an instrument dedicated to a single test is weighed against an instrument that performs on a broader platform, Dr. Carter says. While Nichols’ system is dedicated to rapid PTH, DPC’s Immulite analyzer can do many other assays with different software, including regular PTH as well as assays for other hormones, enzymes, and tumor markers, to name a few. "Our turnaround is typically 27 minutes, which includes transport and any problems with the instrument," Dr. Catrou says. "One problem with doing the assay so infrequently is that the system must fine-tune specimen transport from the operating room to the central laboratory. Transport time can vary anywhere from two minutes to 20 minutes." Dr. Carter says many hospitals are apparently finding it more efficient to work at rapid transport of specimens and results rather than move testing to the operating room. At Pitt Memorial, the surgical suite is roughly 300 feet away from the laboratory. According to laboratory protocol, Dr. Catrou says, "we meet a person from the operating room halfway and should have a transport time of less than five minutes." But, he notes, if the specimen had to come from the ambulatory surgery center, which is half a mile away, that transport time would be impractical. A key factor in intraoperative testing is the need to run quality controls—which can take 17 to 30 minutes—as close to the time of the operation as possible. "The laboratory has to have advance notice of the surgery, because for us to have rapid turnaround time, controls have to be run in advance so the instrument is ready," Dr. Carter says. "We have run into a situation at this hospital where the surgeon wanted a rapid PTH intraoperatively and the laboratory didn’t know about it beforehand." Surgeons at the National Institutes of Health perform about one to two parathyroidectomies per week, says Glen L. Hortin, MD, PhD, chief of clinical chemistry at NIH’s Warren Magnuson Clinical Center and former chair of the CAP Point-of-Care Testing Committee. Alan T. Remaley, MD, PhD, director of the immunoassay laboratory at the NIH, calls the intraoperative PTH assay "almost indispensable" for the NIH’s patient population. "The NIH treats a lot of patients with multiglandular disease and patients with ectopic glands, who were not adequately treated in prior surgeries. We use the assay in all of our cases, and it frequently leads to changes in the surgical management of patients," Dr. Remaley says. The NIH initially performed the assay in the operating room with the Nichols cart assay, but it now performs the assay in the central laboratory. In collaboration with Nichols Institute Diagnostics, the NIH developed a rapid PTH assay on the Nichols Advantage analyzer, which is an automated immunoassay instrument. "Our central laboratory is adjacent to the operating rooms, so it was more convenient for us to do the assay on a standard analyzer in the main laboratory," Dr. Remaley says. The decision on where it’s best to perform the assay depends on many factors that are "likely to vary from institution to institution, such as staff availability, complexity of the cases, and the specimen transport time from the operating rooms to the central laboratory," Dr. Remaley says. Point-of-care instruments can be simple where waived technology is involved, Dr. Carter says. "But this is not a waived test. The instruments can be very difficult to operate," and a qualified person is needed to perform the test. Some states might actually require a certain certification level for such a complex test, but even in general, says Dr. Hortin, "It’s more suited for a medical technologist to run because it’s fairly technique-dependent and requires handling of calibrators, significant knowledge of instruments, and appropriate timing when moving the samples from mixing to measurement." A better level of automation would be required to get away from needing a medical technologist, he says. Some studies have shown, however, that despite the high cost of rapid point-of-care PTH assays, the net savings are substantial. Researchers at the Washington University School of Medicine, for example, studied an experimental group of patients for whom intraoperative rapid PTH assays were between $55 and $113. Comparing this group with a historical control group, the researchers found significantly fewer frozen sections, shorter hospital stays, greater use of local anesthesia, and more unilateral rather than bilateral neck explorations.2 Improvements to the test could further increase its usefulness in the operating room. "One issue that’s starting to raise its head in the PTH arena over the last couple of years is molecular forms of PTH which are not the intact molecule but which are detected by the PTH assay," says Dr. Catrou. PTH consists of an 84 amino acid polypeptide, and the surgeons’ main interest is measuring this intact molecule. "But there are fragments of PTH we have been having difficulty with for many years in assays," he says. When PTH is secreted from the gland, he explains, it’s released as an intact active molecule. "What happens once it’s out in the blood is that it’s fairly rapidly degraded by enzymes and primarily excreted by the kidneys. It can degrade into different fragments, none of which are biologically active. One of these fragments has a very short aminoterminal truncation of the first six amino acids [PTH(7-84)]." "We’re calling the latest assay ’intact PTH,’ but it turns out that even the Nichols and the Turbo assays will actually respond to large PTH fragments that are not the complete molecule," he continues. "These fragments of PTH, including the PTH(7-84) fragment, can markedly be increased in patients with renal failure and cross-react with the assay. So if you get an answer of 100 picograms per milliliter of hormone, it won’t all be the intact molecule, and it’s the intact molecule we’re interested in." "Say you have someone with renal failure with a lot of PTH(7-84) in the blood. You might not see your 50 percent decrease when you take out that parathyroid because the assay may be measuring those smaller fragments as well as the intact molecule." Although in general the assays have done very well, Dr. Catrou says, "I’ve seen up to 50 percent cross-reactivity, so in certain cases your assay is going to be 50 percent incorrect." Getting a new assay that measures the entire molecule from amino acids 1 to 84 is an area that is being researched. In fact, Nichols Institute Diagnostics released in December 2001 a standard PTH assay, called the Bio-Intact PTH(1-84), that recognizes only the intact (1-84) PTH molecule. Dr. Remaley at the NIH is evaluating a rapid version of this new assay on the Nichols Advantage analyzer for use during parathyroidectomies. The poll attached to the CAP Special Ligand Survey found considerable variation in testing practices for parathyroid surgery, and Dr. Hortin suggests that more evaluation is needed to determine the optimal use of intraoperative PTH testing. Of 355 laboratories reporting PTH testing results, 92 said they offer intraoperative PTH testing, and 81 of those reported the percentage of time it was used. Forty percent said it was used for every case, 31 percent use it for a majority of cases, and in 30 percent of the laboratories it is used for selected cases. However, PTH testing remains far and away the most common intraoperative hormone measurement and may serve as a model for other tumors. Only four laboratories responding to the CAP Survey poll indicated they perform intraoperative testing for other hormones. The clinical laboratory at the NIH, for example, has developed and now performs rapid immunoassays for insulinomas, ACTH-producing endocrine tumors, and cortisol-producing tissue. Over the next few years, intraoperative PTH testing practices could change again, Dr. Hortin notes. "If immunoassay analyzers become smaller, cheaper, and easier to operate, tests may migrate back into the operating room," he says. "We saw from our survey that the types of commercially available products strongly influence the site of testing." References Anne Paxton is a writer in Seattle. The full results of the 2001 poll of laboratories participating in the CAP Special Ligand Survey will be published in an upcoming issue of the Archives of Pathology & Laboratory Medicine in an article written by Drs. Hortin and Carter. |
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