American Association for Clinical Chemistry
Better health through laboratory medicine
January 2008 Clinical Laboratory News: Diagnostic Profiles

  
January 2008: Volume 34, Number 1


Population Data Fails to Establish TSH Reference Range

Analysis of data from a large population study has failed to determine an accurate thyroid-stimulating-hormone (TSH) cutoff because occult thyroid dysfunction skews the upper TSH limit, according to a recent paper (Journal of Clinical Endocrinology 2007; 92: 4236–4240). To evaluate factors influencing the TSH reference range, researchers from the University of Southern California in Los Angeles, Calif., University of Kansas Medical Center in Kansas City, Kan., and Boston University in Boston, Mass. studied the relationships between TSH, thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies in 14,202 white, Mexican-American, and African-American people age 12 and older who participated in the NHANES III, did not report thyroid disease or taking thyroid medications, and whose total T4 was within the reference limits. TPOAb prevalence was lowest (<3%) when TSH was between 0.1 and 1.5 mIU/L in women and between 0.1 and 2.0 mIU/L in men and progressively increased to above 50% when TSH exceeded 20 mIU/L. In analysis of TSH reference range parameters—2.5th, 50th, and 97.5th percentile—according to thyroid antibody status and race/ethnicity, the inclusion of antibody positive subjects increased TSH medians and upper limits (97.5th percentile) across all age groups in each ethnicity. The TSH upper limit was lower for the entire African-American cohort, versus whites and Mexican-Americans. This difference remained when researchers compared age cohorts with a similar prevalence of TPOAb (African-Americans ages 40–49 versus white and Mexican-Americans ages 20–29). “The current study shows that it is not possible to establish an accurate TSH upper limit from population data such as NHANES III. Furthermore, because TSH has a low index of individuality (the ratio between the within- and between-person variability), the TSH population reference range is not expected to be a sensitive parameter for detecting thyroid dysfunction in individuals,” researchers wrote. They suggested adoption of a TSH upper limit of 3.0 mIU/L, as recommended by the American Association of Clinical Endocrinologists, because it is consistent with the range of TSH associated with the lowest TPOAb prevalence in both men and women.


 H-FABP Predicts Risk After ACS

 
Heart-type fatty acid-binding protein (H-FABP) predicts long-term mortality after acute coronary syndromes (ACS) and identifies high-risk patients, adding useful information to clinical risk factors and levels of troponin and CRP, according to recent research (Journal of the American College of Cardiology 2007; 50: 2061–2067). To determine if a high-performance assay for H-FABP, which is released following myocardial ischemia and necrosis, has a role in predicting all-cause mortality after ACS, researchers from the Leeds Institute for Genetics, Health & Therapeutics in the U.K. measured H-FABP in a population-based cohort of 1,448 patients 12 to 24 hours after onset of symptoms. After 12 months of follow-up, 296 patients died. Multivariate analysis showed that H-FABP quartiles strongly predicted outcome. The adjusted HRs for H-FABP quartiles were 1.0 for quartile 1; HR 2.32 (95% CI, 1.25–4.30) for quartile 2; HR 3.17 (95% CI, 1.73–5.82) for quartile 3; and 4.88 ( 95% CI; 2.67–8.93) for quartile 4. The crude all-cause 1-year mortality for unstable angina patients with H-FABP<5.8μg/l was 2.1%, compared with 22.9% for patients above this cutoff. The adjusted all-cause mortality HR in this group was 11.35 (95% CI, 2.00–64.34). “In contrast with other prognostic markers, such as hs-CRP and B-type natriuretic peptide, H-FABP provides direct evidence not only of acute myocyte necrosis, but also of myocardial ischemia,” researchers wrote.
 

 Genetic Tests Aid Warfarin Dosing But Don’t Reduce Out-of-Range INRs

Using an algorithm guided by both pharmacogenetic and clinical factors improved the accuracy and efficiency of initial warfarin dosing, but did not reduce out-of-range internal normalized ratios (INRs), according to new research (Circulation 2007;116: 2563–2570). However, subgroup analysis suggested that pharmacogenetic guidance might help keep INRs in normal ranges for patients without any variant genotypes or with multiple variants. Researchers from LDS Intermountain Healthcare and University of Utah in Salt Lake City randomized 206 patients to standard or pharmacogenetic-guided therapy that followed a regression equation including three genetic variants, along with age, sex, and weight. During follow-up, the researchers measured prothrombin time INR at baseline and routinely on days 3, 5, 8, 21, 60, and 90, while a pharmacist managed dose adjustments. Initial doses made with pharmacogenetic guidance required fewer and smaller subsequent adjustments, because they more accurately approximated stable doses. But percent out-of-range INRs, the study’s primary endpoint, did not differ significantly between the two study arms. For the standard care group, that figure was 33.1%, compared to 20.7% for the pharmacogenetic-guided care group. However, among subsets of patients with wild-type genotypes, who require larger doses, and those with multiple variants, who need smaller doses, the percentage of out-of-range INRs was smaller among those patients who received pharmacogenetic-guided care. Together, these two subsets experienced a 10% reduction in out-of-range INRs with pharmacogenetic guidance, from 39% to 29%. “These initial randomized findings will be valuable as the basis for further evaluation of pharmacogenetic-guided warfarin therapy, including the design and sizing of additional randomized trials,” the researchers wrote.


Study Yields Mixed Findings on Vitamin D and Cancer

A large prospective study failed to link total cancer mortality to serum vitamin D levels, but it did conclude that colon cancer mortality was lower among those participants with higher serum levels of the nutrient (Journal of the National Cancer Institute 2007; 99: 1594–1602). In this first prospective study to examine the relationship between vitamin D and cancer mortality, researchers from the National Cancer Institute and the National Center for Health Statistics examined data collected from 1988 through 2000 from 16,818 adult participants in NHANES III. Researchers measured levels of serum 25-hydroxyvitaim (25(OH)D)—a form of vitamin D that circulates in the blood—at baseline by radioimmunoassay and used Cox proportional hazard regression models to examine the relationship between 25(OH)D levels and total cancer mortality and deaths from specific cancers in the entire study population. Because serum was collected in the South in cooler months and in the North in warmer ones, the researchers examined associations by collection seasons. The team identified 536 cancer deaths in 146,578 person-years. Total cancer mortality was unrelated to baseline vitamin D status in the entire population, and in non-Hispanic whites, non-Hispanic African-Americans, and Mexican-Americans, thereby disproving a hypothesis that low vitamin D levels in blacks contribute to racial disparities in cancer mortality. The researchers found no interaction between vitamin D and season or vitamin D and serum retinol. Colorectal cancer motility was inversely related to serum 25(OH)D level, with levels >80 nmol/L or higher associated with lower risk (95% CI, 0.11-0.68), compared with levels >50 nmol/L. The researchers called for more large studies of measured 25(OH)D serum levels to confirm their findings regarding total cancer mortality and to get more accurate risk estimates for death from specific cancers.