Grading and Staging in Gastroenterology

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This means that AUCs obtained in different studies should not be compared directly, but a unifying correction for the stage distribution should be performed first. Obviously, this fact reflects on the conclusions that can be made by comparison of the AUC-evaluated performances of non-invasive tests. Moreover, it is important to bear in mind that the biopsy itself has an AUC, which could be derived from the "true gold standard" studies of entire section of the liver [ 34 ].

Therefore, the performances of non-invasive biomarkers with AUCs comparable to liver biopsy' own AUC are difficult to compare and verify. In the absence of studies involving whole liver sectioning, some of the proposed candidate biomarker may, in fact, reflect the overall fibrosis within the liver better than the liver biopsy itself. The rate of adoption of non-invasive diagnostics for liver fibrosis differs from country to country, but remains limited. At present, the use of non-invasive procedures could be recommended as pre-screening tools, which may allow physicians to narrow down the patients' population before definitive testing of liver fibrosis by biopsy of the liver Figure 2.

Decision tree that may help to guide the cost-effective diagnosis of liver fibrosis in large populations of prospective patients. The activation of HSCs and deposition of the ECM leads to alterations in liver microstructure that are reflected by an increase in the liver stiffness and changes in the blood flow. An ultrasound-based technology for quantitatively assessing hepatic stiffness has been introduced in the last several years both in Europe and other parts of the world and is consistently gaining traction.

FibroScan measures the stiffness or elasticity of the hepatic parenchyma using both ultrasound 5 MHz and low-frequency 50 Hz elastic waves produced by a specialized ultrasound vibrator applied to the body wall and coupled with 1D ultrasound imaging that measures the propagation speed of a wave using a pulse-echo ultrasound.

Since fibrotic tissue is harder than healthy liver tissue, the shear wave measurement provides immediate quantitative assessment of the "degree of stiffness" which takes less than 5 minutes to collect. Most of the FibroScan studies originate in Europe where this method was invented and approved for use in routine clinical settings. FibroScan was reported to be of value in the diagnosis of the fibrosis accompanying various liver diseases including hepatitis B and C, alcoholic liver disease, and non alcoholic fatty liver disease NAFLD [ 35 , 36 ].

However, for the diagnosis of significant fibrosis, there was a high variation of the AUCs dependent on the underlying liver disease [ 36 ]. Similar to serum-based tests, transient elastography can be repeated over time, thus, providing an opportunity for longitudinal disease monitoring and comparative assessments that are difficult when the primary diagnostic means is a liver biopsy.

FibroScan technology is not free of limitations. Most importantly, its accuracy in predicting significant cirrhosis is influenced by necroinflammatory activity and steatosis common in patients with NAFLD [ 38 ]. To improve the performance of FibroScan, its combination with serum based FibroMeter test was suggested [ 39 ].

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According to large series of liver stiffness measurements that included 13, individual examinations, these measures remain impossible to interpret in nearly one in five cases [ 40 ]. The success rate of the procedure is dependent on observer expertise as well as on age of the patient, the width of the inter-costal space, the presence of ascites, the body mass index of patient and presence of visceral adiposity [ 40 , 41 ]. ARFI imaging combines conventional unltrasonography of the liver with evaluation of local liver stiffness. As regions of evaluation can be chosen using ultrasound, ARFI allows operator avoidance of anatomical obstacles, e.

Other studies compared ARFI to Forns' index and other non-invasive, clinical parameters-based diagnostic tests, and found that in hepatitis C patients ARFI' diagnostic ability was superior to any of these [ 46 ]. An important advantage of ARFI is that it can be performed with software integrated into conventional ultrasound equipment as opposed to purchasing expensive TE-enabling Fibroscan units. MRI technology can be used to measure both liver stiffness and characteristic water-diffusion abnormalities associated with cirrhosis [ 47 ]. It should not be confused with magnetic resonance spectroscopy MRS , which provides images of the metabolic abnormalities in subjects with liver disease.

Several types of enhanced MRI have been developed to evaluate the degree of liver fibrosis. One such modification, Magnetic Resonance Elastography MRE directly visualizes and quantitatively measures acoustic shear waves progressing through the liver tissue. MRE involves a three-step process:1 generating mechanical waves within the tissues of interest; 2 imaging the micron level displacements caused by propagating waves using a special MRI technique with oscillating motion-sensitizing gradients; and 3 processing the wave images using an inversion algorithm to generate quantitative maps of the physical properties of the liver [ 48 ].

Importantly, MRI accurately reflects the distribution of the fibrous material in the liver, thus, at least in some cases helping with identification of the nature of injury [ 8 ]. The current evidence support the observation that a normal mean liver stiffness value by MRE in the setting of chronic liver disease is consistent with stage 0 fibrosis on liver biopsy [ 48 ], while fibrosis of stages are also diagnosed accurately [ 48 — 50 ].

In a study encompassing 50 patients with biopsy-proven liver disease and 35 healthy volunteers, receiver operating characteristic ROC analysis showed that, with a shear stiffness cutoff value of 2. Notably, stage I fibrosis detection was possible; while the detection of hepatic fibrosis with stages 2 or more, the area under the ROC curve AUC was 0. The only practical limitation of performing MR elastography in very obese patients is that the patient has to fit within the magnetic bore, the diameter of which is also further reduced by the presence of the transducer.

Furthermore, MRE use can be limited for claustrophobic patients or those with severe hemochromatosis. These limitations preclude MRE from wide spread clinical acceptance and its primary purpose remains a research. In recent years, interest in identifying and describing liver fibrosis by using non invasive surrogate markers has been on the rise.

Serum markers of liver fibrosis offer an attractive, cost effective alternative to liver biopsy for both patients and clinicians. In addition to being substantially less invasive, there are practically no complications, little or no sampling errors and small observer related variability. Moreover, measurements may be performed repeatedly, thus, allowing for a dynamic monitoring of fibrosis [ 51 ]. A majority of commonly used biomarkers were identified in the past two decades in relatively low-throughput clinical studies centered on the pathogenic mechanisms. Recently, the process of biomarker discovery was augmented by a number of commercial high-throughput pipelines aimed at singling out the molecules differentially expressed between various physiological and pathological states followed by validation of their performance in independent cohorts and true translation from bench to bedside as pre-packaged diagnostic kits.

While the first step on this path, the discovery of new biomarker leads, produced a variety of promising candidates, assessing each biomarker in a statistically significant number of samples and controls still constitutes a major technical challenge. Another problem is the fair assessment of relative value of novel biomarkers or biomarker panels as compared to existing non-invasive predictors. Typically, the performance of each novel biomarker is compared to that of either one or more other panels, and the assessment is limited to one pathological condition i.

Given this approach, the exact contribution of each newly described biomarker to the prediction of liver fibrosis is difficult to evaluate. A recent study of Park and coauthors specifically addressed this question and concluded that the simultaneous addition of several biomarkers adds only modestly to clinical predictive factors for the risk assessment of individual patients [ 52 ]. The diagnostic value of serum markers of liver fibrosis has been investigated in numerous studies.

Based on clinical and research needs, the ideal marker for liver fibrosis would have the following characteristics:. Be applicable to the monitoring of disease progression or regression as apart of natural history of liver disease or treatment regimens. Not be susceptible to false positive results, for example, in individuals with inflammation related to other diseases.

Although no single ideal marker exists, several markers have been identified as possible useful indicators of fibrosis when used in conjunction with each other. Biomarkers of fibrosis are commonly divided into Direct and Indirect markers. Direct markers are fragments of the liver matrix components produced by hepatic stellate cells HSC during the process of ECM remodeling. Direct and indirect markers may be used alone or - more commonly - in combination with each other, to produce composite scores. The calculation of such scores can be relatively simple or can be based on complicated formulas e.

In the healthy human liver the most abundant collagens are the fibril-forming types I and III. In its mature form, the collagen is integrated into the ECM. During fibrogenesis, type I collagen levels increase up to eightfold. Its relative concentration in the basement membrane is higher in hepatic fibrogenesis and is closely followed by an increase in its serum level [ 55 ].

Unfortunately, PIIINP is not specific for the fibrosis of the liver as it is also elevated in acromegaly, lung fibrosis, chronic pancreatitis, and rheumatologic disease [ 54 ]. MMPs form a family of structurally related proteolytic enzymes that mediate the degradation of the ECM and the basal membranes [ 56 , 58 ].

During hepatic fibrogenesis, the expression of MMP-2 is markedly increased. The potential for MMP-2 for predicting liver fibrosis remains unclear as some contradictory data have been reported by studies performed so far [ 60 , 61 ].

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In one of the studies, MMP-9 levels were negatively correlated to the histological severity of the liver disease in patients with chronic hepatitis C [ 63 ]. These findings prompt using serum TIMP-1 as a non-invasive assay in liver fibrosis [ 63 ]. YKL chondrex is a mammalian homologue of the bacterial chitinases involved in remodeling or degradation of the extracellular matrix [ 66 ]. In liver diseases, serum levels of YKL are closely related to the degree of histologically documented fibrosis [ 67 ]. Laminin is a major non-collagenous glycoprotein synthesized by the HSC and deposited in the basement membrane of the liver.

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During fibrosis, laminin accumulates around the vessels, in the perisinusoidal spaces and near the portal tract [ 68 ]. Elevated levels of laminin and pepsin resistant laminin laminin P1 were found to correlate with the degree of perisinusoidal fibrosis [ 69 ]. However, serum CTGF levels decrease in the end-stage cirrhosis [ 70 ]. Paraoxonase 1 PON-1 is an enzyme that hydrolyzes lipid peroxides, has antioxidant properties and influences hepatic cell apoptosis.

Measurement of serum PON1 activity has been proposed as a potential test for the evaluation of liver function, however, it clinical acceptance is limited due to instability and toxicity of its substrate, paraoxon [ 71 ]. Ferre ant coauthors [ 72 ] showed that baseline and stimulated PON1 activities are decreased in chronic hepatitis and in liver cirrhosis.

Microfibril-associated glycoprotein 4 MFAP-4 is a ligand for integrins. They reflect the rate of matrix turnover not only deposition and have a tendency to be more elevated when associated with high inflammatory activity. As a consequence, extensive matrix deposition might not be detected in the presence of minimal inflammation;. They are not liver-specific and their serum levels may be elevated in the presence of concomitant sites of inflammation;.

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Serum levels of markers depend on their clearance rates, which are influenced by the dysfunction of endothelial cells, impaired biliary excretion or renal function [ 53 ]. Most Indirect biomarkers of fibrosis are integrated with one or more fibrosis predicting biomarker panels. Aspartate aminotransferase AST and Alanine aminotransferase ALT are hepatic enzymes that are released into the bloodstream from damaged hepatocytes.

However, overall accuracy of this index is relatively low [ 76 , 77 ]. However, recent large meta-analysis suggested that APRI can identify hepatitis C-related fibrosis with only a moderate degree of accuracy [ 79 ]. This method can be used to differentiate patients with mild F0-F1 fibrosis from those with severe F2-F4 fibrosis, but it is less accurate in distinguishing patients with grades F2 versus F4.

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The Forns index has been validated in other cohorts as a predictive tool for response to anti-HCV therapy [ 80 ]. Importantly, HepaScore test can be automated using a single analyzer [ 81 ]. Using a cut off of 0. At the other end of the spectrum, a cutoff of less than 0.

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