American Association for Clinical Chemistry
Better health through laboratory medicine
November 2007 Clinical Laboratory News: Diagnostic Profiles

November 2007: Volume 33, Number 11

HbA1c Predicts Disease in Nondiabetic Women

In support of recent recommendations for lowering diagnostic thresholds for glucose metabolic disorders, recent research shows that elevation of HbA1c levels occurs well in advance of the clinical development of diabetes (The American Journal of Medicine 2007; 120: 720–727). To determine if mild increases in HbA1c provide prognostic information for patients at usual risk for diabetes, a multi-site team of researchers examined baseline HbA1c levels as a predictor of incident clinical diabetes and cardiovascular disease (CVD) in 26,353 Women’s Health Study participants who had not been diagnosed with diabetes or vascular disease and were at least 45 years old. During a median of 10.1 years of follow-up, 1,238 cases of diabetes and 684 cardiovascular events occurred. In age-adjusted analyses using quintiles of HbA1c, researchers observed a risk gradient for both incident diabetes and CVD. After multivariate adjustment, HbA1c remained a strong predictor of diabetes and was no longer significantly associated with incident CVD. In analyses of threshold effects, adjusted relative risk for incident diabetes in HbA1c categories of less than 5.0%, 5.0%–5.4%, 5.6%–5.9%, 6.0%–6.4%, 6.5% –6.9%, and 7.0% or more were 1.0, 2.9, 12.1, 29.3, 28.2, and 81.2, respectively. Risk associations persisted after additional adjustment for CRP levels and after excluding individuals who developed diabetes within 2 and 5 years of follow-up. “Our findings demonstrate the potential prognostic importance of this biomarker at levels generally considered either normal or only mildly elevated in usual clinical care,” researchers wrote. “Although these data do not support the use of HbA1c as a single measure of diabetes risk, our results do suggest that the prognostic significance of elevated HbA1c may warrant a greater emphasis in primary prevention.”

 Warfarin Dosing Algorithm for Orthopedic Patients Incorporates Genetics

A new genetically based warfarin dosing algorithm may make the drug safer for orthopedic patients, according to a recent paper. (Blood 2007; 110: 1511–515). Noting that same-day genotyping is not available in many institutions, researchers from Washington University in St. Louis (Mo.) noted that their algorithm allows physicians to prescribe a conservative first dose before receiving genotyping results. The researchers developed their algorithm during a study of 92 men and women (median age 58.2) scheduled for primary or revision total hip replacement. After collecting blood samples, preoperative and postoperative laboratory values, and information about clinical variables and current medications, the researchers genotyped patients to determine if they had polymorphisms in the CYP2C9 and VKORC1 genes. The investigators used stepwise regression to develop a model for refining dosage after patients had three warfarin doses. The algorithm, which incorporated eight factors associated with higher therapeutic warfarin doses, explained 81.5% of variation in dosage. The more significant predictors included INR value after three doses, first warfarin dose, CYP2C9 and VKORC1, estimated blood loss, and smoking status. Researchers noted that previously published pharmacogentic warfarin dosing algorithms explain 51% to 60% of variability, but require that the genotype be readily available. If an initial warfarin dose is not excessive, physicians may have a 3-day window for obtaining patients’ genotypes, they maintained. A free, interactive version of the algorithm is available online, but researchers cautioned that the algorithm must be validated.

 New High Sensitivity TnT Assay Is Useful in Heart Failure

Very low TnT levels can predict adverse outcomes in heart failure patients, according to a recent paper (The American Journal of Medicine 2007; 120: 720–727). To test the prognostic value of a highly sensitive precommercial assay that detects circulating TnT (hsTnT) with a detection limit of ≤0.001 ng/mL versus a traditional troponin assay (cTnT) that is sensitive to ≤0.01 ng/mL, Italian researchers and colleagues at three U.S. institutions measured plasma TnT in 4,053 patients with CHF who participated in the Salsartan Heart Failure Trial (Val-HeFT). Using hsTnT, the team detected the marker in 92.0% of patients, versus 10.4% of patients using cTnT. Patients with cTnT elevation or with hsTnT above the median, 0.012 ng/mL, had more severe heart failure and worse outcomes. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death and first hospitalization for heart failures (780 events, HR 2.08, 95% CI 1.72–2.52 and 665 events, HR 1.55, 95% CI, 1.25–1.93, respectively). Very low levels of TnT detected with the hsTnT assay were associated with risk of death in unadjusted analysis for deciles of concentrations and in multivariable models (HR 1.05, 95% CI, 1.04–1.07 for increments of 0.01 ng/mL). Addition of hsTnT to well-calibrated models adjusted for clinical risk factors, with or without BNP, significantly improved prognostic discrimination. “These results demonstrate that serial measurements of hsTnT may be of clinical relevance for the management of patients with chronic heart failure,” researchers wrote.

Troponin Assay with Improved Sensitivity Allows Earlier Detection of MI

A new, more sensitive assay for cardiac troponin I (cTnI) detects myocardial injury earlier than the present generation test from the same manufacturer and is likely to allow earlier identification of high-risk patients with ACS, recent research concludes (American Journal of Clinical Pathology 2007; 128: 282–286). While cTnTs are important biochemical markers for determining myocardial injury, a major limitation is the time they take to rise to detectable levels. So researchers from Brigham and Women’s Hospital (Boston, Mass.) compared a new, more sensitive troponin assay, Centaur TnI-Ultra, (Siemens Medical Solutions, Diagnostics Division, Tarrytown, N.Y.) to a traditional cTnI assay. Researchers used their laboratory information systems to identify patients who initially had one or more negative cTnI specimens (<0.10 ng/mL) followed by one or more positive results (≥0.10 ng/mL) within 24 hours, and then collected discarded plasma specimens from this cohort of patients. These included both the initially negative cTnI sample and all subsequently negative cTnI samples drawn within 72 hours from the first cTnI test. Researchers also reviewed medical records to determine patients’ clinical diagnoses. In all, researchers analyzed a total of 356 specimens from men of median age 68 using both the cTnI and TnI-Ultra assays. With TnI-Ultra, they achieved a 10% coefficient of variation at a concentration of 0.03–0.04 ng/mL, whereas the same coefficient of variation required only concentrations of 0.10–0.12 ng/mL for the cTnI assay. TnI-Ultra showed positive results before cTnI in 64% of samples. “In our study population, we found that reporting TnI-Ultra results would allow the diagnosis of cardiac injury to be made an average of 9 hours sooner,” the researchers wrote. “It is important to note that the ability to provide earlier detection for more than 50% of patients who were subsequently confirmed to have ACS at initial examination has the potential to substantially enhance early triage in the emergency setting and provide clinicians the opportunity to begin appropriate therapy for high-risk patients as early as possible.”

B7-H3 Ligand Has Potential in Predicting
 Prostate Cancer’s Course

B7-H3 ligand expression is an independent predictor of prostate cancer progression following surgery and a novel diagnostic and potential therapeutic target for clinical management, according to a recent trial (Cancer Research 2007; 67: 7893–7898). While previous research shows B7-H1 expression by carcinomas of the kidney and bladder, they have not been investigated in prostate cancers. Accordingly, researchers from the Mayo Clinic (Rochester, Minn.) evaluated B7-H3 and B7-H1 protein expression in pathologic specimens from 338 men treated for clinically localized prostate cancer with radical retropubic prostactectomy. Expression levels of B7-H3 in their prostate cancers were correlated with pathologic indicators of aggressive cancer as well as clinical outcomes. B7-H3 was uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelialneoplasia, and four prostate cells lines, while B7-H1 was rarely expressed there. Increasing levels of B7-H3 intensity correlated with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 19.8% of specimens, conferred more than a 4-fold risk of cancer progression after surgery (RR 4.2). “Immunohistochemical assessment of B7-H3 expression in prostate biopsy specimens may prove useful to refine the precision of existing prognostic algorithms,” researchers wrote, calling for more investigation of the marker’s role determining the course of prostate cancer.