Trends in Clinical Chemistry

Vol. 20 • Issue 12 • Page 38

Clinical chemists must continue to stay abreast of new biomarkers, disease discoveries and more. Here, we review some of the major areas having the most dramatic impact this year.

Liver Disease

“With great advancements in the therapeutic modalities used for the treatment of chronic liver diseases, the accurate assessment of liver fibrosis is a vital need for successful individualized management of disease activity in patients. The lack of accurate, reproducible and easily applied methods for fibrosis assessment has been the major limitation in both clinical management and research in liver diseases. However, the problem of the development of biomarkers capable of noninvasive staging of fibrosis in the liver is difficult; the process of fibrogenesis is a component of the normal healing response to injury, invasion by pathogens, as well as other etiologic factors.”1

Current noninvasive methods range from serum biomarker assays to advanced imaging techniques. Among noninvasive methods that have gained the strongest clinical foothold are FibroScan elastometry and the serum-based FibroTest. Many other biomarkers have not been widely validated but are promising.

Presently, use of noninvasive procedures could be recommended as pre-screening that may allow physicians to narrow down the patients’ population before definitive testing of liver fibrosis by biopsy of the liver. Poynard2 in a meta analysis found that FibroTest (eight studies, 1,842 patients) and Fibroscan (five studies, 618 patients) were commonly used for the diagnosis of advanced fibrosis.

Additional markers were studied by Valva et al.3 who reported that “in adults given the diagnostic accuracy of HA, PIIINP and TGF-á1, their combination may provide a potential useful tool to assess liver fibrosis. This first pediatric study suggests that TIMP-1 is clinically useful for predicting liver fibrosis in HCV patients.”

Kidney Disease

Although cystatin C assays have taken their rightful place as excellent markers of kidney function, particularly when coupled with one of several validated GFR calculations, Nguyen suggested that it “is probable a serum panel comprised of NGAL and cystatin C and a Devarajan P. urine panel (NGAL, interleukin 18 [IL-18] and kidney injury molecule 1 [KIM]-1) will be used to evaluate acute kidney injury. As they represent sequentially expressed biomarkers, it is likely that the AKI panels will be useful for timing the initial insult and assessing the duration of AKI. Based on the differential expression of the biomarkers, it is also likely that the AKI panels will distinguish between the various types and etiologies of AKI.”4

Screening for Cancer

The debate on prostate-specific antigen (PSA) screening continues. Current evidence is insufficient to warrant widespread population-based screening by PSA for PCa. A systematic prostate biopsy under ultrasound guidance and local anaesthesia is the preferred diagnostic method.

Stabler and his coworkers5 found that higher serum homocysteine, cystathionine and cysteine concentrations independently predicted risk of early biochemical recurrence and aggressiveness of prostate cancer in a nested case control study. The methionine metabolites further supplemented known clinical variables in providing superior sensitivity and for rapid biochemical recurrence following prostatectomy. Concurring results presented data suggesting that free amino acid profiling has great potential for improving cancer screening and diagnosis and understanding disease pathogenesis.

As well, screening women for BRCA1 and 2 is helpful in the treatment of women who are positive for either or both mutations in these genes. The guidelines are:

• Ashkenazi Jewish women (whose ancestors came from Eastern Europe). Some experts recommend gene tests for women who are of Ashkenazi Jewish descent if they have one or both of the following:

• any first-degree relative with breast or ovarian cancer and/or

• two second-degree relatives on the same side of the family with breast or ovarian cancer.

If a person is not of Ashkenazi Jewish descent, some experts recommend a genetic test if the person has one or more of the following:

• two first-degree relatives with breast cancer, one of whom was diagnosed before age 50;

• three or more first- or second-degree relatives with breast cancer, diagnosed at any age;

• both breast and ovarian cancer in the family;

• a first-degree relative with cancer in both breasts;

• two or more relatives with ovarian cancer;

• one relative with both breast and ovarian cancer; and/or

• a male relative with breast cancer.

Speaking to bladder cancer, Khochikar6 argued that “although we do not have an ideal marker for bladder cancer, it is time we maximize the potential of markers such as UroVysion, NMP22 along with cytology to start such a program.” Maybe as a first step the early detection and screening program could be started in high-risk population. It is not worth waiting until we find the best marker, as it would be unfair to our patients. The fear of unnecessary tests and treatment in bladder cancer after its detection in screening program is without any substance. The cost-effectiveness of such a program is certainly comparable to that used for colon or breast and for prostate as well.

One commercial detector of circulating tumor cells (CTC) can detect 1 CTC in 7.5 mL of peripheral blood, with high reproducibility. In the U.S., clinical trials have used this system to detect CTCs in patients with metastatic breast cancer, metastatic colorectal cancer and metastatic prostate cancer, and CTCs have been confirmed to be a useful prognostic factor.7 This system was also suggested to be useful for monitoring treatment response in patients with metastatic breast cancer and was approved by FDA 2004.

Measuring CTC counts can facilitate the early prediction of treatment response and thereby avoid unnecessary therapy. CTCs may also be a useful biomarker for molecular-targeted agents, enabling the identification of patients most likely to respond to a given treatment and facilitating treatment selection. However, the widespread use of CTC monitoring as a routine examination requires a further improvement in measurement sensitivity, the establishment of criteria for quantitative and qualitative evaluations, and additional clear-cut evidence supporting the clinical significance of CTCs. We expect that CTCs will be established to be a new diagnostic and therapeutic index for breast cancer.

Cardiac Markers

Cardiac markers are used in the diagnosis and risk stratification of patients with chest pain and suspected acute coronary syndrome (ACS). The cardiac troponins, in particular, have become the cardiac markers of choice for patients with ACS. Indeed, cardiac troponin is essential to the definition of MI in the consensus guidelines from the American College of Cardiology (ACC) and the European Society of Cardiology (ESC).

For example, patients with elevated troponin levels but negative creatine kinase-MB (CK-MB) values who were formerly diagnosed with unstable angina or minor myocardial injury are now reclassified as non-ST-segment elevation MI (NSTEMI), even in the absence of diagnostic electrocardiogram (ECG) changes.7

Similarly, only one elevated troponin level above the established cutoff is required to establish the diagnosis of acute MI, according to the ACC guidelines for NSTEMI.8 These changes were instituted following the introduction of increasingly sensitive and precise troponin assays. Up to 80% of patients with acute MI will have an elevated troponin level within 2-3 hours of emergency department (ED) arrival, versus 6-9 hours or more with CK-MB and other cardiac markers.

David Plaut is a chemist and statistician in Plano, TX. Audrey Quinleaven is a medical technologist and histologist in Ithaca, NY.


1. Baranova A, Lal P, Birerdinc A, et al. Non-invasive markers for hepatic fibrosis. BMC Gastroenterol 2011; Aug 17;11:91.

2. Curr Poynard T, Ngo Y, Munteanu M, et al. Noninvasive markers of hepaticfibrosis in chronic hepatitis B Hepat Rep 2011 June;10(2):87-97.

3. Valva P, Casciato P, Diaz Carrasco JM, et al. The role of serum biomarkers in predicting fibrosis progression in pediatric and adult hepatitis C virus chronic infection. PLoS One 2011; 6(8).

4. Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 2008 Dec;23(12):2151-7.

5. Stabler S, Koyama T, Zhao Z, et al. Serum methionine metabolites are risk factors for metastatic prostate cancer progression. PLoS One 2011; 6(8):e22486.

6. Khochikar MV. Rationale for an early detection program for bladder cancer. Indian J Urol 2011;27(2):218-25.

7. Twerenbold R, Reichlin T, Reiter M, Mller C. High-sensitive cardiac troponin: Friend or foe? Swiss Med Wkly. 2011; May 10;141 See also Clinical application of sensitive cardiac troponin assays: Potential and limitations. Biomark Med 2010 Jun;4(3):395-401.

8. National Academy of Clinical Biochemistry LabMedicine Practice Guidelines: Use of Cardiac Troponin and B-Type Natriuretic Peptide or N-Terminal proB-Type Natriuretic Peptide for Etiologies Other than ACS and Heart Failure NACB WRITING GROUP MEMBERS, Alan H.B. Wu, Clin. Chem., 53: 2086 – 2096, 2007.

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