Contrast of Traditional Marker and New Markers of Liver Fibrosis - Essay Example

? Compare and Contrast Traditional Marker and New Markers of Liver Fibrosis of the Under the guidance of Harvard styleWord Count: Date of submission Compare and Contrast Traditional Marker and New Markers of Liver Fibrosis Abstract Liver fibrosis is a consequence of chronic damage to the liver due to one or more causes like chronic hepatitis C infection, non-alcoholic steatohepatitis and alcohol abuse and has the potential to progress to advanced liver conditions like liver failure, cirrhosis and portal hypertension, requiring liver transplantation. Management of liver fibrosis is mainly based on the accuracy of the degree of liver fibrosis and those with chronic liver disease need to be frequently evaluated for detection of liver fibrosis in early stages. Traditionally, liver biopsy was considered to be the "gold standard" test for ascertaining and evaluation liver biopsy. But is is fraught with several disadvantages and recent novel methods claim to overcome the disadvantages associated with liver biopsy. In this research article, both traditional and novel methods of liver biopsy evaluation are discussed. Novel assessment strategies include serological assays, imaging methods and genetic studies. There are 2 types of biochemical markers and they are direct and indirect. Direct markers evaluate for fibrolysis and fibrogenesis. There is evidence to show that there does exists a good correlation between different biochemical markers, suggesting the fact that they investigate similar process. While the role of biochemical markers are studied and many researchers have opined that they are better than liver biopsy, currently liver biopsy still enjoys the first line investigation method for diagnosis and staging of liver fibrosis. Imaging studies and genetic studies are also considered useful, but in research stage. Excessive accumulation of various extracellular matrix proteins like collagen is known as liver fibrosis. The condition arises because of chronic damage to the liver due to one or more causes like chronic hepatitis C infection, non-alcoholic steatohepatitis and alcohol abuse. It has the potential to progress to advanced liver conditions like liver failure, cirrhosis and portal hypertension, requiring liver transplantation (Bataller and Brenner, 2005). As of now, there is no standard treatment for liver fibrosis. Though some treatments have been found effective among rodents, they have not been practical to apply on humans because of the difficulties associated with performing serial biopsies to evaluate and ascertain the changes associated with treatment accurately and also because of the fact that humans are much less sensitive towards antifibrotic treatments when compared to rodents (Bataller and Brenner, 2005). Currently, the most effective treatment for liver biopsy appears to be removal of the offending agent and the only curative approach for those with cirrhosis and complications is liver transplantation which improves not only the quality of life, but also the survival (Bataller and Brenner, 2005). Management of liver fibrosis is mainly based on the accuracy of the degree of liver fibrosis. Those with chronic liver disease need to be frequently evaluated for detection of liver fibrosis in early stages. Traditionally, liver biopsy was considered to be the "gold standard" test for ascertaining and evaluation liver biopsy. However, this test is fraught with several limitations and risks because of the invasive nature of the procedure. Recent investigations like biochemical tests, liver magnetic resonance imaging and genetic evaluation are non-invasive and overcome the disadvantages of liver biopsy. However, some experts continue to employ liver biopsy for evaluation of liver biopsy arguing that it is a more accurate assessment strategy. In this research article, both traditional and modern methods of liver fibrosis evaluation will be compared and discussed through review of suitable literature. A brief overview of the pathogenesis of the disease will be provide to enhance the understanding of the role of various investigatory methods. Liver fibrosis is an insidious condition and morbidity and mortality related to the disease occurs subsequent to development of cirrhosis (Benyon and Iredale, 2000). However, it takes about 15-20 years for cirrhosis to develop after onset of liver fibrosis. Liver fibrosis is basically a response to repeated liver injury. Following an acute liver injury process, regeneration of the parenchymal cells occurs and these replace the apoptotic or necrotic cells. This is associated with severe inflammatory repose and deposition of the extracellular matrix. Initially, the deposition of the matrix is limited. However, repeated injury triggers excessive deposition of the matrix due to failure of liver regeneration. Major collagen producing cells in liver fibrosis are portal fibroblasts, activated hepatic stellate cells and myofibroblasts (Higuchi and Gores, 2003). Activation of these cells occurs because of the action of certain fibrogenic cytokines like angiotensin II, TGF-beta-1 and leptin (Bataller and Brenner, 2005). The type and distribution of extracellular matrix deposited is dependent on the type of liver injury. For example, in chronic cholestatic disorders and chronic viral hepatitis, the distribution of the matrix is around the portal tracts; while in alcoholic liver disease, the distribution occurs in the perisinusoidal and pericentral regions. Progression of fibrosis manifests as collagen bands and then to bridging fibrosis, ultimately leading to frank cirrhosis. Liver fibrosis is associated with alterations of not only the quantity but also the composition of extracellular matrix. The inflammatory mediators and the composition of extracellular matrix are different for different etiologies (Bataller and Brenner, 2005). It is very important to assess and evaluate the degree of liver fibrosis to not only stage and establish the diagnosis, but also to prognosticate and take therapeutic decisions. Traditional methods of liver fibrosis investigation include liver biopsy and subsequent studies like classical histological evaluation and immunohistochemical studies. Needle biopsy of the liver is the gold standard test for assessment of liver fibrosis and provides useful information. However, this test is fraught with several technical and diagnostic limitations. The size of the biopsy needs to be adequate. Ideal sample size is 14mm wide and 20mm long, containing about 11- 15 complete portal tracts. Other than the size requirements, other limitations include perfect histological technique application, non-fragmented sample and a connective tissue stain that is impeccable. The stage of the fibrotic process is determined by analysis of the extracellular matrix using immunohistochemical analysis. Deposition of tenascin is a marker for fibrogenesis that is active. Whereas, vitronectin indicates mature fibrotic tissue and it is likely that this tissue does not regress (Grigorescu, 2006). Liver biosy is costly, invasive and subject to variability of sampling and complications (Faria et al, 2009). In view of the above limitations associated with liver biopsy, several alternative methods which are mainly noninvasive have been developed to assess liver fibrosis. This is very important because; as of now, there is no standard laboratory analysis method or any virologic essay or imaging strategy that can distinguish individuals heading towards progressive fibrosis from those who are in a non-progressive stage. Identification of novel investigation methods are important for four reasons (Grigorescu, 2006): 1. Advanced fibrosis has lower response rate for antiviral treatment. 2. The determination of the stage of fibrosis through noninvasive test can be a good indicator to decide upon initiation of antiviral treatment. 3.The time of development of cirrhosis can be ascertained. 4. The prognosis of the disease, progression, response o treatment and regression can be evaluated by easy non-expensive and non-invasive tests. Novel assessment strategies include serological assays, imaging methods and genetic studies. Various serological assays include direct and indirect markers and cytokine profile. Imaging techniques include magnetic resonance imaging, ultrasonography, computed tomography and elastography. Biochemical noninvasive tests discriminate those with absent or insignificant fibrosis (Metavir, F0 and F1) from those individuals who have significant liver fibrosis (Metavir,F2-F4) without the need to undergo biopsy. Most of the biochemical markers have accuracy rates between 0.8- 0.85 (Grigorescu, 2006). They have more value in ascertaining whether the fibrosis is significant or not rather than the staging of fibrosis. Indeterminate results are found in F1 and f2 stages of liver disease. Thus, biochemical markers are not useful for staging (Grigorescu, 2006). There are 2 types of biochemical markers and they are direct and indirect. Direct markers evaluate for fibrolysis and fibrogenesis. There are markers both for cytokines and matrix metabolism. There is evidence to show that there does exists a good correlation between different biochemical markers, suggesting the fact that they investigate similar process. The direct marker levels are increased rapidly progressive fibrosis. When the disease is responsive to treatment, the levels of the markers decrease in correlation with response. Also, there does exist an independent correlation between direct markers and staging of fibrosis. Thus, direct markers are useful in staging the disease, in predicting the progression of the disease and assessing response to medical treatment (Grigorescu, 2006). In this regard, direct markers that are associated with deposition of the matrix are Procollagen type I carboxy terminal peptide, Procollagen type III amino-terminal peptide, Serum type IV collagen, laminin, hyaluronic acid and YKL-40. Those associated with matrix degradation are matrix metalloproteinases. Chemokines and cytokines associated and useful in the diagnosis of liver fibrosis are TGF-?1, Platelet derived growth factor and others. Several researchers have proposed a combination of direct markers for evaluation and staging of liver fibrosis. Markers which have been specifically evaluated for this purpose are laminin, NP, PIII, hyaluronic acid and TGF-?1 (Oberti et al, cited in Grigorescu, 2006). Other non-specificmarkers which can be correlated with these are a2-macroglobulin, GGT, prothrombin index and apolipoprotein A1 (Oberti et al, cited in Grigorescu, 2006). In yet another study by Fabris et al (Grigorescu, 2006), the authors reported that PIIINP and collagen IV were associated independently with cirrhosis. Murawaki et al (Grigorescu, 2006) opined that PIVNP and HI were useful in diagnosing fibrosis above F2 stage. Direct serum markers are associated with several limitations. The levels are elevated when there is high inflammatory activity. Thus, when there is minimal inflammation, extensive matrix deposition may not be identified. Since most of them are not liver specific, concomitant presence of inflammation at other sites can elevate their serum levels. Since they are dependent on clearance rates, their values are influenced in renal dysfunction, biliary excretion impairment and endothelial dysfunction (Grigorescu, 2006). Indirect markers of liver fibrosis are serum ALT levels, AST / ALT ratio, platelet count and prothrombin index. Other markers include pseudocholinesterase, fibronectin, manganese superoxide dismutase and N-acetyl-b-glucosamini-dase. Some researchers have obtained correct classification results upto 81 percent with these markers (Grigorescu, 2006). Poynard et al (2004) conducted a study to summarise the diagnostic value of biochemical markers for fibrosis of liver related to chronic hepatitis C infection. A systematic review of various published literature was done in this regard. From the data analysis and results of the study, it was evident that biochemical arkers are useful alternatives for liver biopsy for assessment of the extent of liver injury in those with chronic hepatitis C infection. The authors of the study opined that biochemical markers like Fibrotest must be recommended for evaluation of chronic hepatitis C liver injury and that liver biopsy must be recommended only when there is increased risk of error in biochemical evaluation. Similar opinion was delivered by Ratziu et al (2006). These researchers determined the diagnostic value of non-invasive markers like fibrotest in the validation of liver fibrosis related to chronic hepatitis C infection and alcoholic liver disease. Zaman et al (2007) evaluated prospectively the role of a panel of serum biochemical markers, known as FIBROSpectSM II which consisted of tissue inhibitor of metalloproteinases 1, hyaluronic acid and hyaluronic acid, all 3 of which are fibrosis markers, in the assessment and determination of liver fibrosis when compared to liver biopsy. The study supported the fact that serum markers are useful alternatives for liver biopsy for evaluation of liver fibrosis. These markers are especially useful in ruling out fibrosis when there are high negative values. In the study, the sensitivity of the FIBROSpect II was 71.8 percent and the specificity was 73.9 percent. This was in a study population in which liver fibrosis prevalence was 36.1 percent. The positive predictive values for this prevalence was 60.9 percent and the negative predictive value was 82.3 percent. From Figure-1, it is evident that as the baseline prevalence falls, the negative predictive value rises. The overall accuracy of the biochemical assay and the sensitivity and specificity do not appear to change over a prevalence range that is wide. For positive result, the likelihood is 2.75 and for negative result it is 0.38. Another interesting point in this figure is, when the cutoff for significant fibrosis is changed to F3-F4, the sensitivity becomes 81.8 percent, specificity 62-9 percent, positive predictive value 20 percent and negative predictive value 96.8 percent. In figure-2, the area under the curve is 0.826 and is much higher than the chance alone, which is 0.5. Figure-1: Performance characteristics of the cohort in terms of negative predictive value (NPV), positive predictive value (PPV) based on the prevalence of significant fibrosis (F2-F4) (Zaman et al, 2007). Figure-2: Receiver Operator Characteristic Curve of the FIBROSpect II Index for differentiating Metavir Stage F0-F1 from F2-F4 (Zaman et al, 2007). The usefulness of these markers have been found even in liver fibrosis related to nonalcoholic steatohepatitis and this is evident from the study by Sakugawa et al (2004). Streinu-Cercel et al (2009) compared liver biopsy with a combination of fibroscan and fibrotest in evaluating liver fibrosis secondary to chronic hepatitis C infection. The accuracy of the results were comparable to liver biopsy and based on these results, the researchers suggested that the combination can be used as a alternative to liver biopsy. According to Stibbe et al (2011), methacetin and galactose breath tests, transient elastography and biomarkers are useful in distinguishing cirrhotic patients from non-cirrhotic patients in liver fibrosis secondary to chronic hepatitis C infection. Several genetic studies have evaluated the role of various gene polymorphisms in determining the progression of liver fibrosis in those with chronic liver diseases. While in alcoholic liver diseases, enzymes and proteins related to metabolism of alcohol have been used for genetic studies, in cholestatic disorders polymorphisms of genes related to inflammatory mediators have been used. In hepatitis C infection, genetic variations related to susceptibility to the infection has been used. Several other gene polymorphisms have also been studies. However, these tests can only predict the progression of the disease. they are not useful for staging the disease or for determining therapeutic application. In regular clinical practice, imaging studies are reserved only for evaluation of hepatocellular carcinoma and portal hypertension, in those who have progressed to hepatic cirrhosis. Imaging tests which have come up in this regard are computed tomography-based texture analysis, ultrasonography-based transient elastography and diverse magnetic resonance (MR) imaging-based techniques (Faria et al, 2009). Imaging techniques which are being developed for noninvasive evaluation of liver fibrosis are conventional contrast material-enhanced MR imaging, MR elastography, double contrast-enhanced MR imaging, MR perfusion imaging and diffusion-weighted imaging (Faria et al, 2009). According to a systematic review by Bonekamp et al (2009), accurate diagnosis and staging is not possible with ultrasonography, although it is frequently used. promising results for staging can be delivered through elastographic measurements using sonography or magnetic resonance. However, currently, only magnetic resonance elastography has been used that too only for diagnosing mild disease or staging. Conclusion Though several non-invasive tests have come up for evaluation of liver fibrosis, liver biopsy continues to be the gold standard for liver fibrosis. Serum markers are useful in those at risk of complications with liver biopsy, in places where expert pathologist to perform liver biopsy is limited, for staging fibrosis to decide on treatment options, for exclusion of cirrhosis and to monitor the progression or regression of liver fibrosis. More research is warranted to make novel methods the standard for evaluation, staging and assessment of liver fibrosis. References Bataller, R., and Brenner, D.A. (2005). Liver Fibrosis. The Journal of Clinical Investigation, 115(2), 209- 218. Benyon, R.C., Iredale, J.P. Is liver fibrosis reversible? Gut, 46, 443–446. Bonekamp, S., Kamel, I., Solga, S., Clark, J. (2009). Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately? J Hepatol., 50(1), 17-35. Grigorescu, M. (2006). Noninvasive Biochemical Markers of Liver Fibrosis. Journal of Gastrointestinal and Liver Diseases, 15(2), 149- 159. Higuchi, H., Gores, G.J. (2003). Mechanisms of liver injury: an overview. Curr. Mol. Med., 3, 483–490. Faria, S.C., Ganesan, K., Mwangi, I., et al. (2009). MR imaging of liver fibrosis: current state of the art. Radiographics, 29(6), 1615-35. Poynard, T., Imbert-Bismut, F., Munteanu, M., et al. (2004). Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comparative Hepatology, 3, 8-15. Ratziu, V., Massard, J., Charlotte, F., et al. (2006). Diagnostic value of biochemical markers (FibroTest- FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterology, 6, 6-12. Sakugawa, H., Nakayoshi, T., Kobashigawa, K., et al. (2005). Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease. World J Gastroenterol., 11(2), 255-259. Stibbe, K.J.M, verveer, C., Francke, J., et al. (2011). Comparison of non-invasive assessment to diagnose liver fibrosis in chronic hepatitis B and C patients. Erasmus Journal of Medicine, 1(2), 7-13. Streinu-Cercel, A., Preotescu, L., Streinu-Cercel, A., et al. (2009). Correlations between non-invasive explorations and liver biopsy in the determination of liver fibrosis in chronic viral hepatitis C. Therapeutics, Pharmacology and Clinical Toxicology, 8(3), 281- 286. Zaman, A., Rosen, H.R., Ingram, K., et al. (2007). Assessment of FIBROSpect II to Detect Hepatic Fibrosis in Chronic Hepatitis C Patients. The American Journal of Medicine, 120, 280.e9-280.e14 Read More