American Association for Clinical Chemistry
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September 2011 Clinical Laboratory News: Diagnostic Profiles

Diagnostic Profiles

No Mortality Benefit from Tight Glycemic Control

A Cochrane Review has concluded that tight glycemic control in type 2 diabetics does not significantly reduce either all-cause mortality or death from heart disease, compared with conventional glycemic control (The Cochrane Library 2011;6 DOI: 10.1002/14651858.CD008143.pub2). Intensive glycemic control does, however, reduce the risk of both lower extremity amputation and microvascular complications while increasing the risk of hypoglycemia.

The investigators evaluated evidence from 20 randomized clinical trials involving 16,106 type 2 diabetics subjected to intensive control, and 13, 880 patients with routine glycemic control. The mean age of participants was 62.1 years and the duration of intervention ranged from 3 days to 12.5 years. The relative risk of all-cause mortality in patients with intensive glycemic control versus conventional glycemic control was 1.05, while the relative risk for cardiovascular death was 1.06.

Targeted glycemic control reduced the relative risk of amputation, retinopathy, retinal photocoagulation, and nephropathy in comparison to routine glycemic control. However, patients subjected to tight glycemic control had increased risks of both mild and severe hypoglycemia, albeit with “substantial heterogeneity” in the findings. In trials dealing with glycemic control in the usual care setting, tight glycemic control was associated with a significant reduction in non-fatal myocardial infarction, but “more trials are needed before firm evidence is established,” according to the authors.

Based upon their review of evidence, the authors suggest clinicians approach lowering patients’ blood glucose cautiously, weighing both the benefits and harms.

iFOBT Predicts Lower, but not Upper, GI Tract Lesions

A large, population-based study of asymptomatic adults indicates that immunochemical fecal occult blood testing (iFOBT) is specific for predicting lesions in the lower gastrointestinal (GI) tract, but not the upper tract (CMAJ 2011. DOI:10.1503/cmaj.101248). The study was designed to test the hypothesis that iFOBT has superior specificity for detecting bleeding in the lower GI tract even if bleeding occurs in the upper tract. iFOBT reacts with human globin, a protein digested by enzymes in the upper GI tract.

The study involved 2,796 participants who provided stool samples for iFOBT prior to undergoing colonoscopy and esophagogastroduodenoscopy on the same day. In all, 397 (14.2%) of subjects had a positive iFOBT, of which 58.7% had negative findings on colonoscopy, and 19.7% had an important lesion in the upper GI tract. Of the 28 participants found to have malignant lesions, 27 had positive iFOBT results, while none of the three found to have esophageal or gastric cancer had positive iFOBT results. The presence of a lesion in the lower GI tract was significantly associated with a positive iFOBT, with an odds ratio of 2.59. In contrast, the presence of a lesion in the upper GI tract was not associated with iFOBT positivity, with an adjusted odds ratio of 1.14.

Among patients who had positive iFOBT but negative findings on colonoscopy, the researchers found that these false-positive iFOBT results were associated with use of antiplatelet drugs and having a low hemoglobin concentration. 

Metabolic Syndrome, Liver Cancer Linked

Metabolic syndrome significantly increases the risk of both types of primary liver cancer, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), according to a newly published study (Hepatology 2011;54:463–71). The findings suggest that approaches to control the recent worldwide epidemic of metabolic syndrome could help reduce the burden of liver cancer.

Both HCC and ICC have increased in the U.S., and while risk factors such as chronic hepatitis C virus infection, chronic hepatitis B virus infection, and alcohol abuse have been recognized, about 20–50% of cases still are idiopathic. More recently, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis have been linked to end-stage liver disease and HCC, and both are also associated with metabolic syndrome. This led the researchers to investigate any link between metabolic syndrome and risk of HCC and ICC in the general U.S. population.

The researchers extracted data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)-Medicare database on all patients diagnosed with histologically confirmed HCC or ICC between 1994–2005. As a control, they selected a 5% random sample of Medicare beneficiaries who lived in the SEER registry regions. In keeping with National Cholesterol Education Program Adult Treatment Panel III recommendations, the researchers defined metabolic syndrome as the presence of at least three of the following conditions, including elevated waist circumference, dyslipidemia, hypertension, and impaired fasting glucose.

As expected, infectious etiologies, unspecified viral hepatitis, and chronic liver diseases all were significantly associated with HCC. Metabolic syndrome also was significantly associated with HCC. Bile duct diseases, infectious diseases, chronic noninfectious liver diseases, inflammatory bowel diseases, and smoking all were significantly more common in people who developed ICC, as was metabolic syndrome. The researchers calculated that pre-existing metabolic syndrome confers a statistically significant 2.13- and 1.56-fold increased risk for HCC and ICC, respectively. This increased risk is independent of other risk factors.

Familial Risks for VTE Characterized

A 20-year nationwide analysis of familial risks for venous thromboembolism (VTE) found that familial factors, although influenced by age and sex, are important risks factors for VTE (Circulation 2011; DOI: 10.1161/CIRCULATIONAHA.110.965020). The study shows that VTE is aggregated in families and suggests that there may be value in discerning both the genetic and nongenetic sources of familial aggregation.

Known risk factors for VTE include immobilization, surgery, trauma, pregnancy, malignancy, and taking oral contraceptives, but VTE is considered a complex disease influenced by numerous genetic and environmental factors. Heritability of VTE has been estimated at 50–60%, but defects like protein C and protein S deficiencies are rare and found in <1% of the population. However, the familial risks for VTE have not been well-characterized.

In order to gain a better understanding of familial risks for VTE, the researchers identified all patients hospitalized in Sweden with VTE between 1987 and 2007 using the Swedish Hospital Discharge Register and the Swedish Multigeneration Register. Of 45,352 individuals hospitalized with VTE, 2,393 (5%) were siblings, yielding a familial standardized incidence ratio of 2.45. The absolute risk increased with age, but the familial standardized incidence ratio was 4.77 between ages 10–19, declining to 2.08 at ages 60–69.

A small subset of patients with two or more siblings affected and accounting for just 0.46% of all siblings in the study were at significantly higher risk. More research is needed to discern whether rare thrombotic genetic defects other than deficiencies of antithrombin, protein S, and protein C are factors in this increased risk profile. The researchers estimated that <50% of the 2.45 overall familial risk identified in their study can be explained by alleles currently known to be associated with VTE, suggesting another avenue for further research. The findings also may help guide the design of future genetic studies of VTE.