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B iomarkers As published in CLI December 2005 It is important to diagnose the presence of liver fibrosis and its severity for optimal patient manage- analyte of the month ment. While liver biopsy is the standard method of diagnosis, the procedure is invasive and subject to diagnostic limitations. This article discusses the current role and limitations of direct and indirect serum markers of liver fibrosis and cirrhosis, and considers the improvements which are necessary before assays for such markers can be considered as a diagnostic alternative to liver biopsy. Serum markers of liver fibrosis by Dr I. N. Guha and Prof. J. P. Iredale Fibrosis is part of the innate wound healing response which occurs in injured tissues and represents a final, common pathway of chronic liver disease. Within the liver, fibrosis is characterised by the deposition of extracellular matrix. Current evidence indicates that net deposition of matrix is the result of a balance between synthesis and degradation and constitutes a dynamic process. The evolution of fibrosis to cirrhosis is dependent on a variety of mechanisms including iterative injury, inflammation, angiogenesis, architec- tural disturbance and oxidative stress. The clinical condition of cirrhosis is associated with decreased hepatic function, aberrant haemodynamics and a propensity for malignant transformation. There are a number of reasons why clinicians need to diagnose the presence and severity of fibrosis. Firstly, it will influence if and when treatment should be commenced, eg in chronic hepatitis C. Secondly, it has been proven that the degree of fibrosis will directly determine future prognosis [1, 2]. Thirdly, there is evidence from animal models and clinical studies that fibrosis may be at least in part reversible [3, 4]. This has led to considerable interest in the research and development of antifibrotic medication. The efficacy of this treatment can only be determined by the ability to monitor the progression or regression of fibrosis closely. Finally, cirrhosis is often asymptomatic but diag- nosing this entity is vital in planning the timing for transplantation, screening for complications, eg hepatocellular cell carcinoma (HCC), and gathering accurate epidemiological data to allocate health care resources appropriately. Hitherto the liver biopsy has represented the "gold standard" for diagnosing liver fibrosis and cirrhosis. The biopsy has the advantages of providing more information than simply the amount of fibrosis present in the liver. However, in the assessment of fibrosis alone it has limitations. Histological analysis is subject to sampling error, unsurprising when one considers that on average 1/50 ,000th of the organ is sampled. Liver biopsies taken at laparoscopy ( i.e. under direct vision) show a 30% discordance in staging of fibrosis when sam- ples are taken form right and left lobes in the context of hepatitis C (HCV) - a disease that is believed to have a homogenous distribution in the liver . Furthermore, the absolute value of liver biopsy is limited by intra-observer and inter-observer variability and limitations of using categorical variables to describe a continuous process. When these deficiencies are taken together with the fact that liver biopsy is invasive, and that although it is a relatively safe pro- cedure it is still associated with pain in 20% of patients and severe morbidity in 0.57% , it becomes clear why there has been an intensive search to find accurate non-invasive markers of liver fibrosis. Other developments of effec- tive non-invasive markers of liver fibrosis would markedly facilitate the devel- opment of antifibrotic therapies. Table 1. Examples of direct serum markers of liver fibrosis. Serum markers of liver fibrosis Serum markers can be broadly divided into direct and indirect measures of Direct serum markers liver fibrosis. The direct markers measure constituents of extracellular matrix Table 1 shows examples of direct markers used as surrogates of liver fibrosis. (ECM) or their breakdown products; the indirect markers measure products In addition to hyaluronic acid (HA) and the N-termial peptide of type III pro- that increase or decrease as a result of fibrosis or cirrhosis. collagen ( PIIINP), other examples of direct markers include YKL-40, laminin, As published in CLI December 2005 B iomarkers have diagnostic excellence at the extreme thresholds which encompass only 30- 40% of the study population [Parkes and Guha et al, submitted]. Limitations of serum markers Some of the limitations of serum markers have been discussed above but there are common reasons why both direct and indirect markers may not be achiev- ing the required diagnostic excellence. It is likely that ECM products such as HA are influenced by not only the production within the liver but also extrac- tion by the liver. Moreover, as fibrosis represents a balance of fibrogenesis and fibrolysis, the simple measurement of one aspect of this equation may not be sufficient for a robust diagnostic tool. Indirect markers may rely on parame- ters of functionality such as platelet count, but these may only be altered at critical levels of fibrosis rather than sequential levels of fibrosis i.e. there is a threshold effect. Panel markers are heavily dependent on the characteristics of the derivation population which may explain the discrepancy when they are tested on external cohorts. One of the biggest challenges facing serum markers is however the limitations of the reference standard to which they are being compared, i.e. the liver biop- sy. Any inaccuracies due to the liver biopsy (see above) will compound the deficiencies of the serum markers. As histology is a surrogate for clinical out- come measures, it has been suggested that serum markers should be compared to hard clinical outcomes such as death, bleeding and HCC. However in liver disease, many of the measures take a considerable length of time to evolve making these trials more difficult to undertake. Investigators have therefore tried to reduce the limitations of biopsy (eg taking bigger biopsies, having one central pathologist score all the biopsies etc) to improve the performance of putative surrogate markers. Clinical utilisation of serum markers The present use of serum markers in clinical practice will depend on the dis- ease and outcome measure. For example, the diagnosis of cirrhosis by HA in alcoholic liver disease has an AUROC of 0.93  and can be considered a useful test. In more general terms, serum markers may be useful in addition to biopsy rather than replacing biopsy. If patients have scores above or below extreme thresholds, scores below the lower threshold suggesting no/mild fibrosis and scores above the higher threshold suggesting moderate/severe fibrosis, a biopsy could be potentially avoided. As the majority of the popu- lation tested presently lie between these extreme thresholds, liver biopsy will Table 2. Example of panel markers used to assess fibrosis in chronic hepatitis C. be required in this "indeterminate group", however the total number of biop- sies performed could be potentially reduced. undulin, tenascin and collagen IV. The sensitivity and specificity is dependent on the disease tested eg HA in general is more accurate in differentiating fibro- Serum markers may also have a role in population studies rather than indi- sis in alcoholic liver disease (ETOH) compared to hepatitis C (HCV). viduals. For example, if a potential antifibrotic improved the fibrosis scores Furthermore, the direct markers have greater accuracy in diagnosing cirrhosis of the cohort as a whole but not in individuals, this may demonstrate a cer- but only have moderate accuracy in separating mild from severe disease. tain degree of efficacy. Moreover, they are unable to distinguish more detailed subdivisions of fibrosis. Conclusion Indirect markers It is likely that the accuracy of serum markers will be improved by using them The majority of literature related to serum markers has been performed on in combination with powerful technologies such as proteomics or imaging subjects with chronic hepatitis C. A detailed systematic review by Gebo et al modalities such as elastography or microbubble ultrasound. To be considered  suggested that panel marker tests may offer the most promise in assessing a serious alternative to liver biopsy, they will need to be improved in accura- fibrosis non-invasively. Panel tests consist of markers which have usually been cy, have the ability to differentiate subtler forms of fibrosis and maintain extrapolated by multiple logistic regression in a derivation population (training accuracy when measured in different populations. set) and then applied to separate a population (validation set). Table 2 shows examples of published panel markers for assessing fibrosis in chronic hepatitis C. The data are presented as the area under the receiving operator characteris- References tic curve (AUROC). This is generated by plotting the sensitivity against 1-speci- 1. Yano M et al. 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