April 2008 Clinical Laboratory News: Diagnostic Profiles

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April 2008: Volume 34, Number 4

CRP Indicates Overall Health Status

A recent paper suggests that increased circulating CRP concentrations are both associated with an increased risk of death from several common chronic diseases and a sensitive and valuable nonspecific indicator of an ongoing disease process (Clinical Chemistry 2008; 54: 335–342). German researchers measured CRP at baseline in 3,620 middle-aged men they randomly picked from three study samples from the general population in Greater Augsburg, Germany. The researchers followed the men for an average of 7.1 years and recorded deaths for any reason and counted those from cancer, CVD, and CHD. A total of 408 men died of any cause, and deaths from the specific diseases totalled 196 for CVD, 129 for CHD, and 127 for cancer. In multivariable Cox regression analysis, subjects with CRP levels >3.0 mg/L at baseline showed an almost 2-fold increased risk of death versus those with CRP < 1 mg/L (HR 1.88, 95% CI, 1.41–2.53). HRs were 2.15 for fatal CVD (95% CI, 1.39–3.34), 1.74 for fatal CHD (95% CI, 1.04–2.92), and 1.65 for cancer (95% CI, 1.01–2.68). In contrast, neither total cholesterol nor HDL-C significantly predicted all-cause mortality or cancer mortality, and cholesterol had only modest effect on CVD mortality. “Persistently low CRP concentrations seem to be associated with a good health status,” the researchers wrote..

Special Attention to High CRP Levels Warranted

High CRP levels should prompt close monitoring of patients not only because of substantial short-term risk, but also due to long-term excess risk, according to a recent paper. It suggests that hospitals measure CRP upon admission to identify patients at increased risk of certain unfavorable outcomes (Clinical Chemistry 54: 343–349). Austrian researchers measured CRP in 274,515 hospital patients and followed them for a median of 4.4 years, using all-cause mortality as an endpoint and multivariate Cox regression adjusted for sex and age. Compared to patients with CRP <5.0 mg/L, the HRs for all-cause mortality increased from 1.4 in the 5.0–10.0 mg/L category to 3.3 in the >80mg/L category. CRP was associated with various causes of death, but was more strongly linked with mortality from cancer than from vascular death. Patients age 30 or younger with increased CRP had far worse outcomes than older patients, with a maximal hazard ratio of 6.7, versus 1.7–3.7 for patients older than 60. Both short- and long-term mortality were associated with increasing CRP concentrations.

Thrombogenic and Inflammatory Markers Predict Short-Term Events

Increasing levels of D-dimer and inflammatory biomarkers may signal near-term—but not distant—clinical events, new research suggests (Annals of Internal Medicine 2008; 148: 85–93). A multi-site research team measured D-dimer, amyloid A protein, and CRP annually for 3.4 years in 377 patients with peripheral arterial disease (PAD). The researchers used Cox regression analyses to evaluate associations of biomarkers levels and changes with CVD and all-cause mortality and calculated HRs for each 1-unit increase in biomarker level. The team also adjusted analyses for age, sex, race, comorbid conditions, ankle-brachial index, and other confounders. Twenty percent of patients died during follow-up. Higher levels of D-dimer (HR 1.20, 95% CI, 1.08–1.33), CRP (HR 1.13, 95% CI, 1.05–1.21), and serum amyloid A (HR 1.12, 95% CI, 1.04–1.20) were associated with higher all-cause mortality among patients who died within 1 year after biomarker measurement, and among patients who died 1 to 2 years after measurement. The HRs for this second group were 1.14 (95% CI, 1.02–1.27), 1.15 (95% CI, 1.06–1.24), and 1.13 (95% CI, 1.04–1.24), respectively. Higher levels of each biomarker weren’t associated with all-cause mortality for deaths occurring 2 to 3 years after biomarkers measurement. The researchers saw similar results for CVD mortality, with greater increases in each biomarker associated with higher all-cause and CVD mortality during the following year. The authors called for confirmation of their results in other clinical trials.

TPSA Predicts Long-Term Risk of Prostate Cancer

A study by American and Swedish researchers concludes that a single PSA test taken by age 50 is a very strong predictor of advanced prostate cancer diagnosed up to 25 years later, suggesting that the test might be useful for finding men in need of intensive screening (BMC Medicine 2008 doi:10.1186/1741-7015-6-6). To determine the association between PSA and advanced cancers—defined as clinical stage T3 or higher, or skeletal metastasis—researchers got blood samples from 21,277 men age 50 and younger during 1974–1986 and followed them until 1999. During this time, 498 of the men had prostate cancer diagnoses, 161 of which were locally advanced or metastatic. Researchers selected three controls for each case and tested associations between molecular markers and advanced cancer using conditional logistic regression. Levels of all PSA forms and human kallikrein 2 (hK2) were associated with case status. Total PSA was a strong and statistically significant predictor of subsequent advanced cancer with AUC of 0.791. Two thirds of the advanced cancer cases occurred among men whose PSA levels were in the top 20%, at 0.9 ng/mL or higher. Free to total PSA ratio and hK2, two markers researchers say are associated more specifically with malignancy, were much less predictive than total PSA, a marker associated with both benign and malignant prostate conditions. Findings suggest that “PSA elevation in cases below or at age 50 may be related to a premalignant state, or to a carcinogenic process, rather than the presence of malignant cells in the prostate,” the researchers wrote. 

New Genetic Variant Affects Warfarin Dosage

Variants of the gene CYP4F2 are associated with a clinically relevant effect on warfarin requirement, according to a recent study (Blood 2008; DOI 10.1182/blood-2007-11-122010). A team of researchers from Marshfield Clinic (Wisc.), Washington University in St. Louis, Mo., Third Wave Technologies, and Affymetrix, Inc. used an Affymetrix drug-metabolizing enzyme and transporter panel to identify new genetic variants that affect warfarin dosing. A DNA variant in CYP4F2 was associated with warfarin dose in three Caucasian cohorts totaling 1,051 patients from Wisconsin, Florida, and Missouri who were stabilized on warfarin. In pooled analysis, patients with 2 TT alleles required about 1 mg/day more warfarin than patients with two CC alleles. Researchers noted that their discovery is more likely to benefit Caucasians and Asians than African Americans because the variation is much more common in the first two groups. The research team didn’t describe any clinical model for using CYP4F2 information.

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