The diagnostic accuracy of Fibroscan® for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response

Journal of Hepatology
Volume 59, Issue 2 , Pages 251-256, August 2013

Roberta D’Ambrosio, Alessio Aghemo, Mirella , Maria Grazia Rumi, Maria Francesca Donato,  Valerie Paradis, Pierre Bedossa, Massimo Colombo

Received 12 December 2012; received in revised form 5 March 2013; accepted 8 March 2013. published online 25 March 2013.

Abstract

Background & Aims

Transient elastography (TE) is a validated non-invasive tool to evaluate hepatic fibrosis in patients with hepatitis C virus (HCV) infection. Whether TE may sense changes of liver fibrosis following therapeutic HCV eradication has never been evaluated.

Methods

37 HCV cirrhotics with paired pre- and post-sustained virological response (SVR) liver biopsies (LB) underwent TE at the time of post-SVR LB. Liver fibrosis was staged with the METAVIR scoring system and the area of fibrosis (%) was assessed morphometrically.

Results

Thirty-three patients had valid TE measurements after 61 (48–104) months from an SVR, and 20 (61%) of them had cirrhosis regression. On post-SVR LB, the median area of fibrosis was 2.3%, being significantly reduced from baseline (p<0.0001). Median TE value was 9.8kPa being lower in regressed vs. not regressed patients (9.1kPa vs. 12.9kPa, p=0.01). TE was <12kPa in 5 (38%) F4 patients and in 19 (95%) F3 patients (p=0.0007). The diagnostic accuracy of TE for diagnosing F4 after treatment was 61% sensitivity, 95% specificity, 12.3 LR+, 0.4 LR−, and AUROC 0.77. A significant correlation was found between TE and both fibrosis stage (r=0.56; p=0.001) and morphometry (r=0.56, p=0.001) as well as between fibrosis stage and area of fibrosis (r=0.72, p=0001).

Conclusions

Following therapeutic eradication of HCV, the predictive power of the viremic cut-off of 12kPa was low as a consequence of liver remodelling and fibrosis reabsorption. LB still remains the only reliable approach to stage liver fibrosis following an SVR.

Abbreviations: SVR, sustained virological response, IFN, interferon, HCV, hepatitis C virus, HBV, hepatitis B virus, LB, liver biopsy, TE, transient elastography, LS, liver stiffness, RBV, ribavirin, LSM, liver stiffness measurement, IQR, interquartile ratio, CI, confidence interval, LR, likelihood ratio

Keywords: Sustained virological response, Hepatitis C virus, Cirrhosis regression, Fibroscan®, Morphometry

Source

Fibroscan (ultra-sound hepatic elastography) Review

Provided by NATAP

Download the PDF here

Noninvasive assessment of liver fibrosis (and Biopsy)
Hepatology
June 2011

"The use of FibroTest or TE or MRE imaging will be helpful if evidence for cirrhosis or minimal to no fibrosis is predicted by these tests." http://www.natap.org/2011/HCV/061311_02.htm

Ultrasound-based Hepatic Elastography Origins, Limitations, and Applications

Journal of Clinical Gastroenterology October 2010
CLINICAL REVIEW

Eric B. Cohen, MD* and Nezam H. Afdhal, MD

*Yale University School of Medicine, Department of Digestive Diseases Liver Center, Beth Israel Deaconess Medical Center

"In conclusion, there is an urgent need for noninvasive markers to quantify liver fibrosis. Hepatic elastography is a novel tool that exploits the correlation between liver stiffness and liver fibrosis. It is excellent at making the diagnosis of cirrhosis and at excluding fibrosis87; it is not able to discriminate between the intermediate stages of fibrosis. Several intrahepatic processes confound the accuracy of HE to gauge fibrosis, and it remains to be seen how these processes will influence future research efforts. It is conceivable that instead of absolute cutoffs, a range of values will be used for diagnosis. HE can be helpful for treatment and management decisions.2,82,88 The era of HE used as the evaluator of the natural history of disease, both pretransplant and posttransplant, is now underway. More studies are necessary to delineate the most appropriate clinical scenarios for this useful new tool."

"The original manuscript published by Sandrin et al in 2003 evaluated a cohort of chronic hepatitis C patients, all with abnormal aminotransferase levels.

Importantly, liver stiffness correlated well at both F0 and F4 stages of fibrosis. Perhaps not surprisingly, there was poor discriminatory ability between metavir F1 and F2 stages of fibrosis (Fig. 2). These observations mirror the diagnostic ability of other, noninvasive markers of fibrosis, namely serologic panels. It is unclear what accounts for the overlap within intermediate stages, although it suggests that our current staging system is an oversimplified representation of a more fluid spectrum of disease."

"In general, transient elastography is as good as the serologic markers (Fibrotest, Lok Index, APRI, Prothrombin index, AST/ALT ratio, and platelet count) to diagnose the earlier stages of fibrosis (31). Elastography has superior accuracy in the detection of cirrhosis, with an AUROC of 0.96, versus the serologic markers (AUROC from 0.61 to 0.82) (31). A separate study found that combining HE with a serologic marker of fibrosis, such as APRI, significantly enhanced the prediction of fibrosis stage. However, combinations of 3 or 4 tests led to redundancy and increased cost.22.....

.....With respect to liver biopsy, HE correlates very well with established cirrhosis. Although considered the gold standard, biopsy is susceptible to understaging, and there is the potential for a correlative discrepancy when elastography is suggestive of cirrhosis. The quality of the biopsy is therefore important, and fortunately, most studies incorporate the quality of the tissue sample."

Abstract: A reliable, noninvasive marker to help clinicians evaluate hepatic fibrosis is urgently needed. The liver biopsy, an imperfect gold standard, has recognized limitations including sampling error and interobserver variability. Hepatic elastography (HE) is a novel sonographic method for assessing liver stiffness and has excellent accuracy in making the diagnosis of minimal fibrosis and cirrhosis. Several conditions intrinsic to the pathology of the liver compromise the positive predictive value of HE for fibrosis alone including acute hepatitis, obstructive cholestasis, and passive congestion. Technical considerations that hinder the performance of elastography include an advanced body mass index, the presence of ascites and narrow intercostal spaces. Despite these limitations, elastography has a role in staging fibrosis, prognosis of disease outcome, surveillance, and treatment decisions. HE is now being used in lieu of liver biopsy to investigate the natural history of chronic liver diseases. Additional studies are required to better define the appropriate role of HE in clinical practice.

Liver fibrogenesis is the wound-healing response and "final" pathway of chronic liver disease.1 Accurate staging of fibrosis is valuable for prognosis, treatment decisions, and surveillance of disease progression or regression.2,3 Liver biopsy, currently the gold standard4 has several recognized limitations including sampling error and interobserver variability in interpretation and staging.5 Furthermore, the dynamic process of fibrosis resulting from progression and regression is difficult to capture with biopsy alone.6 The hepatology community is actively researching noninvasive methods of fibrosis quantification.

Hepatic elastography (HE), which uses the novel method of transient elastography (TE), has been extensively evaluated in many different forms of liver disease as a tool to measure liver stiffness as a surrogate for fibrosis. However, as it is not widely available in the United States and is awaiting FDA approval, there is considerable uncertainty about elastometry's niche within the day-to-day practice of hepatology.7 Perhaps the most critical question for clinicians, as multiple methods develop for the evaluation of fibrosis, is how to cost effectively and safely incorporate this multimodality approach into clinical care. The aim of this review is 3-fold: (1) to provide background that sets the stage for the emergence of HE as a leading noninvasive marker candidate, (2) to identify the strengths and weaknesses of HE, and (3) to describe how it is being applied to the clinical and research setting.

A NEED FOR NONINVASIVENESS

Our understanding of liver fibrogenesis has led to new insights that liver fibrosis is not a relentless and progressive condition. Gone is the dogma of fibrosis following a single, common pathway. New insights dictate that clinically significant histologic improvement can occur even in a cirrhotic liver.8 Pathways favoring fibrogenesis include stellate cell activation, the process of epithelial-to-mesenchymal transition (EMT) of hepatocytes and cholangiocytes, activation of resident portal fibroblasts and bone marrow-derived fibrocytes.9 There is additional variability within pathways, with the composition of extracellular matrix (ECM) changing over time. At the earliest stages of fibrogenesis, elements such as collagen-type IV, heparin-sulfate proteoglycans, and laminin predominate, whereas the ECM of more established fibrosis is dominated by fibril forming collagens type I and III.9 There is, however, a definite inability to accurately measure fibrogenesis and fibrosis regression in vivo using any of our currently available technologies. To really look at these dynamic changes, we will probably need to advance molecular imaging of the cells involved in liver fibrosis and regression. Thus it is essential to have an accurate method to quantify the amount of fibrosis regardless of stage, underlying pathway or disease etiology. To this end liver biopsy has been the clinician and investigator's gold standard for decades. Beyond its diagnostic capability, liver biopsy is an invaluable tool for clinical prognostication as it relates to the stage of fibrosis. For a clinician, defining the stage of liver fibrosis provides a general estimation of disease chronicity and severity. Clinically relevant outcomes in liver disease are often a result of advanced fibrosis or cirrhosis, with eventual development of portal hypertension and hepatocellular carcinoma. In fact, septal thickness and small nodularity are 2 histologic features independently predictive of clinically significant portal hypertension (HVPG ≥10).10 In addition, HCC occurs primarily in the setting of cirrhosis and one can argue that the major role of biopsy is in diagnosing or excluding advanced fibrosis and cirrhosis so that appropriate screening can be undertaken.

In addition, the fibrosis stage has been used to determine the relative urgency for disease treatment, especially with highly prevalent, indolent conditions such as hepatitis C virus infection and nonalcoholic steatohepatitis. Valid recognition of the extreme ends of the fibrosis spectrum, therefore, would either allow for a cautious, cost-effective delay of treatment or herald imminent treatment and surveillance for the complications of cirrhosis. This paradigm helps define the utility we seek in noninvasive biomarkers. In effect, categorizing an established diagnosis as early or late in its natural history can add efficiency to treatment algorithms and provide important prognostic information for both the patient and clinician.

However, the need for staging disease is also dependant on the outcome of treatment; as treatment becomes more effective the need for staging disease precisely becomes less necessary and the need to exclude cirrhosis more important. For example, in genotype 2 and 3 HCV, biopsy is not necessary as over 80% of patients achieve a sustained virologic response that is independent of disease stage. In such cases, biopsy can be reserved for those that fail to respond.

A biopsy is said to represent 1/50,000 of the liver,11,12 and therefore it is not surprising that sampling error frequently occurs. The actual frequency is an area of debate; 25% to 30% is commonly ascribed, with understaging occurring especially at the lower strata of fibrosis.13,14 In a recent paper by Robert et al,15 the percentage of disagreement between hepatopathologist and community pathologist assessments for staging hepatitis C ranged between 22 and 58% depending on the stage of fibrosis, and was augmented in biopsy samples less than 1.5 cm. In addition to the propensity for sample error and interobserver interpretation, liver biopsy suffers from poor patient acceptance because it is invasive and sometimes painful.16 Furthermore, there is a small but significant risk for serious complications and death,4 even when carried out transjugularly. Toward the future, as more clinical trials of antifibrotics are designed, serial biopsy will unlikely be the sole evaluator of regression, and therefore, noninvasive methods are paramount.

Mehta et al evaluated a critical aspect in the search for the ideal noninvasive marker of fibrosis.17 Assuming a conservative error rate for biopsy staging of 10% to 20%, how is it possible to validate a perfect alternative when it is compared with an imperfect standard? Their model suggested that the area under the ROC curve for a surrogate marker for fibrosis compared with liver biopsy could not exceed 0.9. In effect, biopsy error causes the true validity of surrogate tests to be underestimated. This will in turn lead a clinician to falsely misperceive the test as inaccurate, when in fact it is possible that a perfect surrogate marker could already exist.

The ideal noninvasive marker should have certain characteristics for practical application. For an imaging modality such as elastometry, salient features should include: ability to accurately determine fibrosis stage; reliability unaffected by the underlying disease and conditions intrinsic to hepatopathology; ease of performance and reproducibility. These characteristics are similar to ones earlier described for serologic markers of fibrosis.18 Studies thus far suggest that HE possesses many of the characteristics of an ideal marker, and will be elaborated in this review.

ELASTOGRAPHY AND FIBROSIS STAGING

The evolution of elastography in the field of hepatology took many forms over nearly 2 decades before finding success in HE.19 The methods of static, dynamic and remote elastography were all first attempted without success. The primary reason was the boundary effect, or motion artifact from respiration that interferes with hepatic imaging. Those methods proved more successful with breast19,20 and prostate19 evaluation.

A sentinel study by Yeh et al21 from China, published in Ultrasound and Medical Biology in 2002, laid the foundation for HE when it was shown that liver stiffness positively correlated with fibrosis. Partial hepatectomy specimens were sectioned into blocks and placed on an electronic balance. This balance was connected to a personal computer and acrylic compressor, which was lowered on to the tissue. The compressor then applied intervals of increasing pressure (in kPa), allowing for measurement of the internal displacement of liver tissue. In effect, healthier livers allowed for greater internal displacement whereas cirrhotic livers, stiffer by nature, had less internal displacement.

Interestingly, this correlation was greatest at the ends of the fibrosis spectrum, and suffered from poor discriminatory ability at the middle strata of fibrosis. This dilemma would prove to haunt HE's applicability throughout subsequent clinical investigations.

This technology was initially used in the cheese industry as a way to evaluate the internal stiffness of large blocks of cheese. Echosens (Paris, France) capitalized on the shear elasticity of another soft solid material and developed the now widely used FibroScan unit. The hand-held probe is placed in the intercostal space overlying the right, lateral lobe of the liver. It sends out 2 types of waves. The first, a shear, mechanical wave, propagates through firm tissue quickly, and through healthy tissue more slowly. The second type of wave emitted by the probe is an ultrasound wave. At a depth between 2.5 and 5.5 cm from the skin, successive ultrasound waves reach a propagating shear wave at a given distance apart, depending on the velocity of that initial shear wave (Fig. 1). The distance between the 2 points can then be used to calculate the shear wave velocity, and in turn, through a mathematical model using Young modulus, the stiffness is determined.19 The area of liver surveilled by FibroScan is 100 times that of liver biopsy, and can be expanded by sampling in different intercostal spaces.

The original manuscript published by Sandrin et al in 2003 evaluated a cohort of chronic hepatitis C patients, all with abnormal aminotransferase levels.

Importantly, liver stiffness correlated well at both F0 and F4 stages of fibrosis. Perhaps not surprisingly, there was poor discriminatory ability between metavir F1 and F2 stages of fibrosis (Fig. 2). These observations mirror the diagnostic ability of other, noninvasive markers of fibrosis, namely serologic panels. It is unclear what accounts for the overlap within intermediate stages, although it suggests that our current staging system is an oversimplified representation of a more fluid spectrum of disease. In general, transient elastography is as good as the serologic markers (Fibrotest, Lok Index, APRI, Prothrombin index, AST/ALT ratio, and platelet count) to diagnose the earlier stages of fibrosis (31). Elastography has superior accuracy in the detection of cirrhosis, with an AUROC of 0.96, versus the serologic markers (AUROC from 0.61 to 0.82) (31). A separate study found that combining HE with a serologic marker of fibrosis, such as APRI, significantly enhanced the prediction of fibrosis stage. However, combinations of 3 or 4 tests led to redundancy and increased cost.22

With respect to liver biopsy, HE correlates very well with established cirrhosis. Although considered the gold standard, biopsy is susceptible to understaging, and there is the potential for a correlative discrepancy when elastography is suggestive of cirrhosis. The quality of the biopsy is therefore important, and fortunately, most studies incorporate the quality of the tissue sample.

Transient elastography and biopsy were compared in a group of 100 patients coinfected with HCV and HIV, and diagnostic values were compared by calculating the area under the ROC.23 Liver stiffness was 0.80 (0.72 to 0.89) when discriminating between F 2, 0.93 (0.85 to 1.00) when discriminating between F 3 and 0.99 (0.97 to 1.00) when discriminating between F/=3 was 11 kPa and F4 was 14 kPa.

An analysis of discordance between transient elastography and biopsy was conducted and an association with liver disease related factors was determined.24 Thirty-four percent of 300 patients had discordant findings, the majority of which had histologic stage >/=2 and TE<7.1 kPa (false negative). A smaller group had stage <2 and TE>7.1 kPa (false positive). Importantly, no patient with discordant results had cirrhosis.

As noted above, the intermediate stages of fibrosis do not correlate well with histology. This may be in part owing to the heterogeneous patterns of fibrosis, that is, periportal, pericellular, and perivenular. It is well recognized that conditions such as hepatitis C and nonalcoholic steatohepatitis lead to different patterns, periportal and pericellular, respectively. A published morphometric analysis revealed a higher correlation between liver stiffness measurement and pericellular fibrosis (r=0.43) than periportal (r=0.21) or perivenular fibrosis (r=0.25).25 The variable nature of fibrosis patterns are more likely to play a role in these intermediate stages of fibrosis, compared with established cirrhosis, in which the architectural distortion is homogenous and the underlying etiology more difficult to discern.

A meta-analysis of 9 studies concurred that the ability to differentiate mild from advanced fibrosis was poor, and was partially explained by a lack of uniformity of stiffness cut-offs between the studies.26 The stiffness cut-off level for cirrhosis from 1 study to the next contains greater variability (from 11 kPa to 19 kPa) than cut-off values diagnosing no or minimal fibrosis, (kPa<7). A recent meta-analysis shows that significant fibrosis, stage F2 or higher, begins around 7.2 kPa.27 Thus interpreting stiffness values at opposite ends of the fibrosis spectrum allows some flexibility without compromising discriminatory ability. The underlying liver disease etiology (viral vs. mixed) and biopsy sample size does not influence the ability to distinguish minimal from advanced disease (22). In contrast, cut-off values for intermediate stages of fibrosis are poorly established. There are too few studies to determine the influence of the specific variables such as disease etiology. Subgroup analyses could not be done reliably (22). Therefore, it can be safely concluded that intermediate stiffness values, between 6 kPa and 9 kPa, do not allow for accurate interpretation of fibrosis stage.

The cut-off values are influenced by disease states and not only the underlying disease itself. In several studies, an "active" disease state is more likely to be reflected by increased stiffness values, and this distinction is critical to accurately interpret stiffness values. The most common active disease state in the study of elastography is inflammation, common to disorders such as viral hepatitis and fatty liver disease. The category of acute viral hepatitis and steatohepatitis will be discussed in separate sections. However, in the case of a chronic active disease such as hepatitis C infection, should an elevated alanine aminotransferase level affect cut-off values? Probably not, however, shifting the cut-off threshold based on an elevated ALT value alone has been attempted. In a prospective study of a hepatitis C cohort, Wong et al25 find that patients with similar fibrosis staging by histology but with higher ALT levels tended to have higher liver stiffness measurements. To account for this observation, the investigators increased the diagnostic threshold for stage 0 to 1 disease (6 kPa if ALT is less than the upper limit of normal; 9 kPa if ALT is 1 to 5 times the upper limit of normal) and stage 3 to 4 disease (7.5 kPa if ALT is less than the upper limit of normal; 12 kPa if ALT is 1 to 5 times the upper limit of normal). A second study also suggests that minor ALT elevations can alter TE readings and cause discordance with histologic stage.28 These observations reinforce the excellent predictive value of stiffness measurements at the extreme ends of the fibrosis spectrum. It also suggests that the continuous spectrum of fibrosis may be independent of ALT values and therefore ranges of stiffness levels may be preferable to absolute cutoffs.

Nearly every study conducted since has corroborated HE's excellent predictive values for the diagnosis of cirrhosis when alternative underlying variables are accounted for29-31 (Fig. 3). The question was bound to arise...could HE be even better than liver biopsy at making the diagnosis of cirrhosis? In a validation study by Nahon et al32 on a cohort of alcoholic liver disease patients, 4 patient's biopsies staged as F3 showed corresponding HE values near 75 kPa, otherwise suggestive of F4 cirrhosis. The investigators suggested that HE did not suffer from poor positive predictive value, rather, the biopsy may have been understaged and these 4 participants might have been cirrhotic. Although no conclusive evidence was offered, this point of contention is noteworthy.

An important meta-analysis by Friedrich-Rust et al33 reaffirmed the conclusion that HE is excellent at making the diagnosis of cirrhosis. The important aspect of this study of more than 50 publications, some only in abstract form, was its inclusion of hepatitis C cohorts, nonhepatitis C cohorts, and mixed-diagnosis cohorts. What these investigators found was that the underlying cause of liver disease had no effect on the ability to diagnose cirrhosis (mean AUROC 0.94), and even severe fibrosis, defined as F>/=3 (mean AUROC 0.89). However, there was considerable variability in accurately diagnosing significant fibrosis (F>/=2) especially in studies with smaller sample sizes. It looked as if the underlying cause of liver disease played a role in stiffness values.

CONFOUNDERS OF STIFFNESS MEASUREMENT

On account of increased stiffness caused by more than just fibrosis, it is clear that pathologic conditions intrinsic to hepatopathology must also be taken into account. Fortunately, much but not all of the groundwork for understanding these potential confounders has been conducted and reported. These include studies on steatosis,32,34,35 hepatitis,36-42 cholestasis,43 infiltrative disorders,44-46 passive congestion47 and more. Recognizing the confounding effect of these conditions is critical to the clinician's interpretation of elastometric results.

Steatosis

Yoneda et al35 appraised the effect of bland steatosis on HE accuracy. It was evident from their results that bland steatosis does not have a confounding effect, regardless of severity. This was also concluded in several other studies,19,29 including one that assessed healthy individuals for the presence of bland steatosis.34 However, when the necroinflammatory component was taken into account, as in the case of NASH, hepatic stiffness increased concomitantly.34 This suggests that NASH, but not NAFLD must be considered carefully when interpreting results. Despite the above conclusions, the literature is not unanimous in its dismissal of simple steatosis. 27,48,49

Hepatitis

The effects of hepatitis per se on HE accuracy have been reported, and there is an emerging consensus on how to interpret elevated aminotransferase levels. Magnitude of elevation and acuity of illness are important variables.37,42,50-53 On one extreme of the hepatitis spectrum, flares of acute or chronic disease, the conclusion is foregone: stiffness is increased.52,53 Sagir et al published a report in 2007 on a cohort of participants with chronic hepatitis B who experienced an acute flare of their disease. Alanine aminotransferase levels ranged from as little as 151 to over 5000 IU/L. These initial values corresponded with HE measurements from 14 to 52 kPa, all within the range of advanced fibrosis or cirrhosis.

Other studies confirmed that stiffness values during a flare are higher than states of chronic viral hepatitis or the inactive carrier.54 These cases were followed longitudinally until resolution of the flare, marked by a return to normal ALT levels, and the liver stiffness levels also decreased to single digit values. Histologic comparisons were not the intention of this descriptive phenomenon. Interestingly, there was a 2-week lag time between the resolution of laboratory parameters (ALT and bilirubin) and stiffness. This finding was not corroborated in a separate study,53 but nevertheless serves as a red flag for cautious interpretation of HE results after flares in disease activity.

Acute flares of hepatitis are one thing, elevated levels from chronic disease55 or even coinfection36 could be another. Castera et al56 report that inflammatory activity does not influence HE values in hepatitis C-infected patients and regression analysis data overwhelmingly supports the claim that ALT levels in chronic disease have no correlation to stiffness.

We have reason to believe that in the cellular milieu of the hepatic lobule during injury, there are additional factors unaccounted for that alter the viscoelastic property. In a revealing study by Georges et al,57 where it was earlier shown that the activation of stellate cells and portal fibroblasts results from increasing substrate stiffness, the same hypothesis was tested in an in vivo rat model of injury with carbon tetrachloride. The investigators found that not only did liver stiffness increase progressively with ongoing liver injury, but that the development of fibrosis lagged behind the development of stiffness. Although it is still unclear what causes this prefibrosis change in stiffness, it is likely that the extracellular matrix undergoes significant dynamic changes with acute injury that is irrespective of the amount of fibrosis. This property is probably one reason for any discrepancy of opinion on the topic of hepatitis and HE accuracy.

Sinusoidal Congestion

Yet another factor intrinsic to hepatopathology is sinusoidal congestion. Passive congestive hepatopathy was highlighted as a case report in a patient with chronic hepatitis C and mildly elevated serum aminotransferase levels.47 Before the cardiac transplant and ostensibly as an evaluation of hepatic reserve, the patient was biopsied after HE revealed a level of 44.3 kPa, highly suggestive of cirrhosis. Histology showed dilated sinusoids and perisinusoidal fibrosis, but periportal fibrosis was limited. Eighteen months after cardiac transplantation, with ALT still mildly elevated, repeat HE revealed a level of just 3.8 kPa, and a repeat liver biopsy confirmed early fibrosis. LeBray et al concluded that congestive hepatopathy lowers the positive predictive value of HE. This study also initiated dialogue about additional factors related to a plethoric liver, such as the use of nonselective ß-blockade, postprandial portal hyperemia, and what effect these have on stiffness.

Extrahepatic Cholestasis

Extrahepatic cholestasis is another variable that has been studied.43 In a series of 15 cases of extrahepatic obstruction, serial HE measurements were used in addition to serum markers of cholestasis. In all but 1 case, biliary stenting was carried out for various causes of obstructive jaundice. Preintervention and postintervention bilirubin levels documented successful resolution of the obstruction. Interestingly, in all but 2 cases, the liver stiffness also decreased postintervention. Of note, several more cases showed only a trivial decrease in stiffness values, but the general trend was such that a firm conclusion was possible. Acute biliary obstruction also accounts for falsely elevated measurements of stiffness.

Extrinsic Factors

There are also conditions extrinsic to the liver that may confound, or, in some cases, altogether preclude the gathering of reliable HE data. The presence of ascites, even in small amounts, negates the applicability of elastography. This, fortunately, is a situation that begs the question. These patients will be cirrhotic by virtue of the presence of their ascites. Advanced age has been reported to affect performance and success of data acquisition.58 Narrow intercostal spaces are another recognized element extrinsic to the liver that makes data acquisition difficult.59 A second-generation probe, engineered for such cases, is in development.

Obesity is also a major hindrance to the practical application of elastography. It is another variable that has attracted much international debate and has yet to be fully resolved. To obtain reliable measurements, the operator must gather a total of 10 elastographic values; successful acquisition must occur 60% of the attempts and the interquartile range of all successful measurements should be less than 30% of the median value.39,49 As mentioned earlier, the probe begins measurement just 2.5 cm from its tip, and therefore, a habitus replete with central adiposity becomes problematic. Again, second-generation probes said to overcome the limits of advanced body mass index (BMI) are in development. The French group led by Castera found that with BMI >30 kg/m2, there is a failed rate (zero successful acquisitions) in 3% of cases, and unreliable results (<60% successful acquisitions or IQR >30%) in 15.8% of cases.60 In other manuscripts, BMI cutoffs of 2861,62 and 3063 are also reported. This last example quoted a failed acquisition rate of 25% when BMI is > 30 kg/m2. In sum, the exact cutoff is not established. This may be owed to the fact that BMI does not always correlate with thoracic adiposity/wall thickness. It also remains to be determined whether unsuccessful acquisition of HE data in itself, owing to overweight, can be used for any predictive value. As several serologic panels of fibrosis markers have been previously validated64 and possess acceptable diagnostic accuracy, their combination with failed HE from obesity could also prove useful.

TOWARD THE NATURAL HISTORY OF DISEASE

Although most research efforts thus far attempted to validate HE against liver biopsy, perhaps an equally apropos translation is to validate HE against the hepatic venous portal pressure gradient, or HVPG. After all, most clinical outcomes in end-stage liver disease are tightly correlated with advanced portal pressures, including detection of esophageal varices, first variceal bleed65,66 and development of hepatocellular carcinoma.67 Several studies validated HE as a noninvasive means of diagnosing portal hypertension.38,68,69

The report by Vizzutti et al70 offers an excellent figure depicting this relationship (Fig. 4). Elastography can indeed diagnose earlier stages of portal hypertension, as the major determinant at gradients between 5 and 12 mm Hg is intrahepatic fibrosis. Beyond this 10 to 12-mm Hg threshold, when the sequelae of elevated portal pressures occur with greater frequency, elastography loses its correlative ability and its well-fitted regression line. The investigator's explanation focuses on the physiologic factors extrinsic to the liver that impact HVPG at these advanced gradients. These factors include portosystemic collateral development, splanchnic vasodilatation, and hyperdynamic circulation. The performance of liver stiffness for predicting significant portal hypertension, defined by HVPG>/=10 mm Hg was found to be 92% predictive with a cutoff of 21 kPa.71 This finding was compared with the accuracy of the prothrombin index, a previously validated serologic marker, and found to be superior. Although the data supporting the ability of HE to diagnose portal hypertension is strong,71,72 the overall data supporting its role in evaluating the consequences of portal hypertension remain unconvincing.73

There has been an inevitable, fundamental shift in the focus of HE studies over the past year toward an investigation into the natural history of disease. This comes as the validation studies and limitation studies reinforce similar conclusions with respect to overall efficacy of HE. These studies by and large aim to exploit elastography's ability to diagnose advanced fibrosis or cirrhosis. One such study looked at hepatitis B virus DNA and ALT levels in HbeAg negative patients to predict cirrhosis.74 The percentage of patients with probable or possible cirrhosis increased with increasing ALT levels, and these findings were subdivided into gender and showed the relative increased risk for males to have HE cirrhosis. Furthermore, DNA evaluation showed a positive correlation with possible and probable cirrhosis, with higher rates corresponding to DNA levels greater than log 6. Other studies predicting advanced fibrosis in cohorts with HCV/HIV coinfection and metabolic syndrome have also been conducted75 with HE as a primary diagnostic tool.

As it is now recognized that significant regression of fibrosis can occur, even in cirrhotic livers, there is great interest in clinical pharmacologic trials for antifibrotics, with no lack of candidates. Of the myriad categories there are inhibitors blocking the activation, migration or proliferation of hepatic stellate cells, hepatocyte maintenance and protection, plant-derived drugs, and even commoner agents such as statins and interferons. One of the first trials using HE to evaluate regression of stiffness as a marker of fibrosis was published in 2008 by Vergniol et al.76 These investigators used standard treatment of Peginterferon and Ribavirin in cases of hepatitis C and measured stiffness before and after treatment. Although the no therapy arm showed no change in stiffness values, each of the 3 study arms showed an effect: nonresponders (10.3% decrease in stiffness), responders/relapsers (29.5% decrease) and sustained virologic responders (24.5% decrease). Although there is no evidence of actual regression of fibrosis, and decreased inflammation can be responsible for decreased stiffness, this study nevertheless proved that HE can be successfully employed to monitor regression of fibrosis in such trials. The liver transplant community also eagerly awaits additional trials using HE. To date, only hepatitis C recurrence has been adequately studied.69,77-79 These trials used protocol liver biopsies anywhere from 1 to 2 years posttransplant and showed accuracy for staging of fibrosis, similar to the hepatitis C in a native liver. Acute viral recurrence immediately after transplant and acute cellular rejection has not been adequately studied, and it remains to be seen whether HE can help differentiate one diagnosis from the other in cases of elevated liver tests at early time points in the liver allograft. In essence this would exploit the other factors that are readily measured by elastography, such as flares of hepatitis and prefibrosis changes in stiffness. Utilization of HE in clinical practice for indications other than fibrosis staging has been suggested.80

With all that has been learned from the studies of HE and the liver since the first publication in 2003, it is now important to ask how this technique can impact day-to-day practice in 2010 and beyond. It seems logical that HE could be used to stage fibrosis from chronic hepatitis C infection. With this diagnostic challenge in mind, some investigators argue that many, if not a majority, of liver biopsies can be avoided altogether. This could amount to a substantial decrease in the overall number of liver biopsies, considering that 50% to 60% of all biopsies are ostensibly for staging purposes.

For example, if HE gives a low value, below 6 kPa, no biopsy is required and serial HE measurements are warranted. This approach seems reasonable. Of participants with a score <5.1 kPa, 93% were stage F0 or F1.19 Moreover, a systematic review found excellent accuracy for diagnosing the earliest stages of fibrosis.81 If HE values suggest cirrhosis and the pretest probability is high, again no biopsy is warranted and the patient could receive appropriate cirrhotic management. For values in the gray zone, between 6 and 9 kPa, a clinician can opt to proceed with biopsy only if treatment is not planned, so as to avoid missing false negative results and the opportunity to treat a compensated cirrhotic patient. If treatment is planned, liver biopsy can be avoided.82 A second paper detailing an algorithm for hepatitis C staging and management offers an additional feature. For these intermediate values, a serologic panel can be added to increase the predictive value. The AST: platelet index (APRI) and Forns Index were suggested.83 As these noninvasive markers have AUROC>0.8 in validation studies64 they may be especially useful in combination with HE for treatment decision-making,56,84-86 such as a second opinion to strengthen an argument against biopsy. It is easy to imagine other scenarios in which HE can be used in lieu of biopsy, such as when biopsy is contraindicated, unavailable or not-preferred by the patient; when the clinician does not believe the interpretation of a biopsy; a baseline HE measurement is obtained in patients with biopsy F0 so that future surveillance can be carried out with HE; pregeneral surgery evaluations; and the list goes on.

CONCLUSIONS

In conclusion, there is an urgent need for noninvasive markers to quantify liver fibrosis. Hepatic elastography is a novel tool that exploits the correlation between liver stiffness and liver fibrosis. It is excellent at making the diagnosis of cirrhosis and at excluding fibrosis87; it is not able to discriminate between the intermediate stages of fibrosis. Several intrahepatic processes confound the accuracy of HE to gauge fibrosis, and it remains to be seen how these processes will influence future research efforts. It is conceivable that instead of absolute cutoffs, a range of values will be used for diagnosis. HE can be helpful for treatment and management decisions.2,82,88 The era of HE used as the evaluator of the natural history of disease, both pretransplant and posttransplant, is now underway. More studies are necessary to delineate the most appropriate clinical scenarios for this useful new tool.

Source

Liver Imaging Tests Vie to Replace Biopsy

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Although biopsy remains the gold standard for diagnosing liver fibrosis, imaging tests increasingly appear to be a viable way to garner equivalent information with less patient discomfort and risk, researchers said here.

In presentations at the meeting of the European Association for the Study of the Liver, scientists from across Europe reported on the strengths and weaknesses of various imaging modalities as tools for routine clinical practice.

There was no clear winner among transient elastography, magnetic resonance elastography (MRE), real-time shear wave elastography (RTSWE), and acoustic radiation force impulse (ARFI) imaging, but all appeared to be nearly as accurate as liver biopsy in quantitative assessment of fibrosis and for predicting outcomes such as death and cirrhotic decompensation.

The role of liver imaging for these purposes in the U.S. has recently come to the fore with the FDA's clearance last week of the Fibroscan transient elastography device. Fibroscan is the established leader in noninvasive fibrosis imaging and, according to its French manufacturer, Echosens, the U.S. is the last major market to approve its device.

All these forms of elastography work by setting up shear waves in the liver. Patterns of propagation of these waves correspond to the degree of liver stiffness, which in turn correlates with the level of fibrosis. All but MRE use ultrasound to generate the waves.

Studies presented here evaluated one or more of these technologies against another, with or without liver biopsy as a reference standard, and in a variety of patient populations.

Transient Elastography Versus Biopsy

Perhaps the most direct assessment was reported by Juan Macias, MD, of Hospital Universitario de Valme in Seville, Spain. He reported a retrospective analysis of 297 patients coinfected with HIV and hepatitis C virus (HCV) who had been tested with liver biopsy as well as transient elastography, with these tests performed within a year of each other. The study period covered 2005 to 2011.

Findings indicated that fibrosis stage as established from biopsies and liver stiffness measurements from transient elastography were equally accurate in predicting overall mortality and decompensation of cirrhosis.

Kaplan-Meier curves for patients with stage F4 fibrosis (overt cirrhosis) and for those with elastography measurements in the highest quintile (21 kPa and above) were nearly identical through up to 6 years of follow-up, for both all-cause death and for decompensation of cirrhosis, Macias reported.

Point estimates of the increased risk for these outcomes were somewhat higher in models based on biopsy findings than in the elastography-based analyses, but the error bars in the latter were markedly smaller.

For example, the risk of decompensation doubled with each increase in fibrosis stage (hazard ratio 2.00, 95% CI 1.32 to 3.00), whereas each 5-kPa increase in liver stiffness corresponded to a hazard ratio of 1.42 (95% CI 1.31 to 1.55).

"The noninvasive nature of [transient elastography] should favor its use instead of liver biopsy when the only issue is predicting the clinical outcome of liver disease in HIV-HCV coinfection," Macias told attendees.

ARFI Versus Transient Elastography

Acoustic radiation force impulse imaging is another up-and-coming imaging method for liver disease. Like transient elastography, it uses ultrasound to generate mechanical waves within the liver, but the nature of the waves and the interpretation of the resultant patterns differs.

Derek Bardou of CHU Angers in Angers, France, noted that the two technologies have been compared head-to-head in previous studies, with pooled data suggesting that ARFI is less accurate.

But transient elastography has a significant drawback -- it doesn't work on obese patients. Bardou pointed out that the previous analyses were all conducted on a per-protocol basis, such that patients for whom the transient elastography attempt failed to yield usable results were excluded.

He argued that a more stringent "intent-to-diagnose" analysis would be a better reflection of the utility of the two methods in routine practice.

From 2009 to early 2013, he and his colleagues used both methods on a total of 267 patients with chronic, noncancerous liver disease (patients with cirrhotic complications or sepsis were excluded) who also underwent liver biopsies. Areas under the receiver-operating characteristic (AUROC) curves for classifying patients' liver disease stage were calculated for both test types, with biopsy results serving as the reference standard.

The researchers found that, on a per-protocol basis, AUROC values with ARFI were indeed lower -- indicating poorer accuracy -- than those seen with transient elastography. In this analysis, Bardou and colleagues excluded 6.7% of patients in whom transient elastography could not be performed. ARFI failed in fewer than 1%.

But in the intent-to-diagnosis analysis involving all 267 patients, there was no significant difference in AUROC values for the two methods.

Bardou added that whole-liver results with ARFI were more accurate than findings only in the right lobe, the "classical" way to perform ARFI, he explained.

RTSWE Versus Transient Elastography Versus Biopsy

Another study reported here sought to validate real-time shear wave elastography as an alternative -- not necessarily superior -- to liver biopsy.

Giovanna Ferraioli, MD, of Italy's University of Pavia, presented findings from 88 patients with chronic liver disease of varied origin and 33 healthy controls.

Patients underwent both RTSWE (using the ElastPQ system) and transient elastography as well as biopsy. The controls had only the noninvasive testing.

RTSWE, in this study, involved a fixed "sample box" located a maximum of 70 mm below the Glisson's capsule within the liver. Patients held their breath for 2 to 4 seconds and 10 images were collected, with the median stiffness value in kPa used as the final result. As the name suggests, and unlike transient elastography, RTSWE delivers readings almost immediately. In some studies, it has appeared to be more accurate as well.

Both imaging methods showed stiffness values that progressed upward with the degree of fibrosis ascertained with the biopsies. RTSWE yielded somewhat more detail, in that the median values for each patient group stratified according to fibrosis stage (F0/1 to F4) tracked steadily higher. Transient elastography results for patients with F2 fibrosis, on the other hand, were nearly identical to those with F0/1 disease (5.45 versus 5.5 kPa).

Ferraioli and colleagues found that, as expected, RTSWE values in the healthy controls were lower than in patients with liver disease (median 3.3 kPa, interquartile range 3.7 to 4.0).

Transient elastography readings tended to be higher (median 3.8 kPa, interquartile range 4.5 to 5.0) and overlapped in the controls with those from patients with liver disease (median in F2 patients 5.45, interquartile range 4.3 to 8.0).

RTSWE "compares favorably" with transient elastography, Ferraioli concluded.

MR Elastography Versus Biopsy

Use of MRI equipment to analyze liver stiffness is an even newer approach. It, too, can be used to generate vibrations that propagate through the liver. Rocio Gallego-Duran, also of the Hospital Universio de Valme, reported on a validation study in which artificial neural networks were used to generate elastography values from MRI scans.

Her study involved 63 patients with biopsy-confirmed non-alcoholic fatty liver disease, including 32 with non-alcoholic steatohepatitis (NASH) and 25 with significant fibrosis.

The first 22 of these patients were used as a "training cohort" for fine-tuning the software settings to match biopsy results as closely as possible. The resulting model was then tested in the remaining 41 patients, serving as a validation cohort.

For diagnosing NASH, the model showed sensitivity of 77% and specificity of 90%, Gallego-Duran reported. Positive and negative predictive values were 89% and 79%, respectively.

The model was not quite as good at diagnosing fibrosis. With the best-performing cutoff values, sensitivity was 87% but specificity was only 63%. As a result, the positive predictive value was just 59%, although the negative predictive value was a respectable 89%.

Gallego-Duran told attendees that the MRI-based technique holds some potential advantages over the ultrasound-based methods. Because it produces high-resolution images of the entire liver, it may provide a fuller picture of liver disease and can also reveal other types of liver injury. Patients' body fat also is not an issue for image quality, as it is for transient elastography, she said.

None of the studies had commercial funding.

All of the presenters declared that they had no relevant financial interests.

Primary source: European Association for the Study of the Liver
Source reference:
Macias J, et al "Performance of liver stiffness compared with liver biopsy to predict survival and decompensations of cirrhosis among HIV/HCV-coinfected patients" EASL 2013; Abstract 20.

Additional source: European Association for the Study of the Liver
Source reference:
Bardou D, et al "First intention-to-diagnose comparison of ARFI and Fibroscan in chronic liver diseases" EASL 2013; Abstract 15.

Additional source: European Association for the Study of the Liver
Source reference:
Ferraioli G, et al "Performance of ELASTPQ^® shear wave elastography technique for assessing fibrosis in chronic viral hepatitis" EASL 2013; Abstract 16.

Source

FDA Approves FibroScan® for Non-invasive Liver Diagnosis

PARIS, April 16, 2013 /PRNewswire/ --

- Echosens™ is pleased to announce that FibroScan® device received 510(k) clearance from the U.S. Food and Drug Administration (FDA) on April 5^th, 2013 and is now ready to market its pioneering technology in the United States.

Today, 1800 FibroScan® devices are used worldwide both in research and routine clinical practice. The United States of America is the last major market to approve FibroScan®.

(Logo: http://photos.prnewswire.com/prnh/20130415/607780-a )

(Photo: http://photos.prnewswire.com/prnh/20130415/607780-b )

FibroScan® is used in the clinical management of patients with liver disease such as chronic viral hepatitis C and B and fatty liver diseases. Based on a technology called transient elastography, FibroScan® assesses liver shear wave speed (expressed in meter per second) and equivalent stiffness (expressed in kilopascal) at 50 Hz in a rapid, simple, non-invasive and totally painless way.

Initially introduced in the European market in 2003, FibroScan® pioneered the quantitative elastography medical field. It received market clearances in China (2008), Canada (2009), Brazil (2010), Japan (2011) and is currently available in 70 countries.

With more than 660 peer-reviewed publications, FibroScan® is by far the elastography device with the largest body of evidence on its clinical usefulness. Moreover, the use of FibroScan® is also mentioned in guidelines and recommendations in different regions of the world: World Health Organization, European Association for the Study of Liver (EASL), Asian Pacific Association for the Study of Liver (APASL), etc.

FibroScan® is manufactured by Echosens™ (Paris, France). Since its foundation in 2001, Echosens™ has gathered strong leadership in quantitative elastography. Very active in research and development, Echosens™ holds 17 patent families mainly focused on its core technology: Vibration-Controlled Transient Elastography (VCTE™).

Contact Echosens™:
Aurélie Houet, Communication Manager
Tel: +33-1-44-82-78-50
Email: aurelie.houet@Echosens.com
http://www.echosens.com

SOURCE Echosens

Source

Scarring Cells Revert To Inactive State As Liver Heals

UC San Diego School of Medicine

A photomicrograph of cirrhotic liver tissue, with extensive fibrotic scarring (stained blue).

Released:5/7/2012 3:40 PM EDT
Source:University of California, San Diego Health Sciences

Research with mice reveals possible strategy to reverse fibrosis in liver and other organs

Newswise — An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, report that significant numbers of myofibroblasts – cells that produce the fibrous scarring in chronic liver injury – revert to an inactive phenotype as the liver heals. The discovery in mouse models could ultimately help lead to new human therapies for reversing fibrosis in the liver, and in other organs like the lungs and kidneys.

The work is published in the May 7, 2012 online Early Edition of the Proceedings of the National Academy of Sciences.

“The take-away message is two-fold,” said David A. Brenner, MD, vice chancellor for Health Sciences, dean of the UC San Diego School of Medicine and senior author of the paper. “First, we’ve shown that liver fibrosis is markedly reversible and we now better understand how it happens. Second, we can start looking for ways to direct active myofibroblasts to stop producing scar, and become inactive. We can focus on developing drugs that promote cell change and regression. It raises the bar for prospective treatment tremendously.”

Liver fibrosis is the 12th leading cause of death in the United States. It is the result of chronic liver injury caused by such agents as the hepatitis B and C viruses, alcoholic liver disease and non-alcoholic steatohepatitis. The condition is manifested by extensive scarring of liver tissue and the organ’s progressive inability to filter body toxins. Liver fibrosis precedes the development of liver cancer. Often, the only treatment for end-stage liver fibrosis is an organ transplant.

Fibrosis begins when infectious agents or excessive alcohol consumption trigger activation of hepatic stellate cells (HSCs), which normally act as quiescent storage units for nutrients like vitamin A in the liver. Once activated, these HSCs acquire characteristics of another cell type called myofibroblasts, which are characterized by their abundant production of extracellular matrix proteins such as collagen. These proteins accumulate as scar tissue, rendering the organ progressively dysfunctional.

However, if the source of the liver injury is successfully treated or eliminated, the liver can repair itself. In part, this is due to the activated HSCs undergoing apoptosis (programmed cell death) and being removed by other cells. But UC San Diego scientists say that, in tests using a mouse model, as many as half of all activated HSCs persist. They do not die, but rather revert to an inactive phenotype during fibrotic regression.

“After one month of regression, these cells have stopped producing collagen. They’ve upregulated some of the genes associated with quiescence and returned to their normal location in the liver,” said Tatiana Kisseleva, MD, PhD, an assistant research scientist and first author of the study.

It’s not clear why these myofibroblasts survive. Also, scientists note the reverted myofibroblasts do not completely return to their original quiescent state. “They’re still more susceptible to repetitive injury than original quiescent HSCs,” said Kisseleva, who noted future tests will investigate whether additional reversion occurs with more time.

Kisseleva suggested the findings present another avenue for treating liver fibrosis, especially in possibly reverting fibrosis and cirrhosis, which accounts for roughly 27,000 deaths in the United States annually.

Fibrosis occurs in other organs as well, such as the kidneys and lungs, with comparable deadly effect. Recent studies indicate fibrotic reversibility in these organs as well. “Our findings are applicable to other fibrosing organs,” said Kisseleva. “Instead of killing damaged cells, we might be able to de-activate them and revert them to healthy originals.”

Co-authors of the study are Min Cong, Chunyan Jiang, Keiko Iwaisako, Brian Scott and Wolfgang Dillmann, Department of Medicine, UC San Diego; YongHan Paik, Department of Medicine, UC San Diego and Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea; David Scholten, Department of Medicine, UC San Diego and Department of Medicine III, University Hospital Aachen, Germany; Thomas Moore-Morris and Sylvia M. Evans, Skaggs School of Pharmacy and Pharmaceutical Science, UC San Diego; Hidekazu Tsukamoto, Keck School of Medicine, University of Southern California.

Source

New fibrosis classification improves accuracy of diagnosis in hepatitis C

January 10, 2012

A new classification for diagnosing fibrosis in patients with chronic hepatitis C virus (HCV) has shown to be as accurate as currently used algorithms, but required no further liver biopsy. The study appearing in the January issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, details a method that synchronously combines two fibrosis tests, providing a non-invasive and more precise fibrosis diagnosis.

HCV affects up to 170,000 million individuals worldwide and is a leading cause of chronic liver disease and a primary indication for liver transplantation according to the World Health Organization (WHO). The Centers for Disease Control and Prevention (CDC) estimates that 2.7 to 3.9 million Americans are living with chronic HCV with roughly 12,000 deaths reported each year. WHO has reported up to 20% of HCV patients develop cirrhosis and 1% to 5% die from cirrhosis or liver cancer.

"Fibrosis progression can be highly unpredictable and accurate classification of the stage of fibrosis is extremely important," said Dr. Jérôme Boursier from Centre Hospitalier Universitaire d'Angers in France. "A diagnostic algorithm that provides similar accuracy as successive classifications without the need of liver biopsy to determine the extent of fibrosis is highly beneficial to patients."

Dr. Boursier and colleagues evaluated the Sequential Algorithm for Fibrosis Evaluation (SAFE) and Bordeaux algorithm (BA), compared to a more detailed classification for determining fibrosis severity. The team used data for 1785 patients with chronic HCV who were enrolled in 3 previous study populations (SNIFF, VINDIAG, and FIBROSTAR), representing a total of 31 centers throughout France. Data included liver biopsy, blood fibrosis test, and Fibroscan—an ultrasound technology used to assess liver fibrosis (stiffness).

The team found that successive SAFE diagnostic accuracy was 87%—significantly lower than the individual SAFE devoted for the diagnosis of significant fibrosis (F≥2) at 95% or for cirrhosis (F4) at 90%. The number of liver biopsies required with successive SAFE was significantly higher than individual SAFE for F≥2 or SAFE for F4 at 71% compared to 64% and 6%, respectively. Researchers also reported similar results with successive BA diagnostic accuracy at 85% compared to individual BA at 88% (F≥2) and 94% (F4). More biopsies were required for successive versus individual BA at 50% compared to 35% and 25%, respectively.

"Our findings show that SAFE and BA diagnostic testing are highly accurate in determining fibrosis or cirrhosis in patients with HCV," said Dr. Boursier. However, a high percentage of patients also required liver biopsy to confirm the diagnosis. The authors creation of a new classification which synchronously combines two fibrosis tests (FibroMeter + Fibroscan) was as accurate as successive SAFE or BA at 87%, and did not require any liver biopsy. "The new non-invasive classification of fibrosis is as accurate as successive SAFE or BA, but is more precise with six fibrosis classes and entirely non-invasive with no liver biopsy required," concludes Dr. Boursier.

More information: "Comparison of 8 Diagnostic Algorithms for Liver Fibrosis in Hepatitis C: New Algorithms are More Precise and Entirely Non-invasive." Jérôme Boursier, Victor de Ledinghen, Jean-Pierre Zarski, Isabelle Fouchard- Hubert, Yves Gallois, Frédéric Oberti, Paul Calès, and multicentric groups from SNIFF 32, VINDIAG 7, AND ANRS/HC/EP23 FIBROSTAR studies. Hepatology; Published Online: December 21, 2011 (DOI: 10.1002/hep.24654); Print Issue Date: January 2012.

Source

Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: The ANRS HCEP-23 study

Journal of Hepatology
Volume 56, Issue 1 , Pages 55-62, January 2012

Jean-Pierre Zarski, Nathalie Sturm, Jérôme Guechot, Adeline Paris, Elie-Serge Zafrani, Tarik Asselah, Renée-Claude Boisson, Jean-Luc Bosson, Dominique Guyader, Jean-Charles Renversez, Jean-Pierre Bronowicki, Marie-Christine Gelineau, Albert Tran, Candice Trocme, Victor De Ledinghen, Elisabeth Lasnier, Armelle Poujol-Robert, Frédéric Ziegler, Marc Bourliere, Hélène Voitot, Dominique Larrey, Maria Alessandra Rosenthal-Allieri, Isabelle Fouchard Hubert, François Bailly, Michel Vaubourdolle, The ANRS HCEP 23 Fibrostar Group

Received 21 October 2010; received in revised form 13 April 2011; accepted 3 May 2011. published online 20 July 2011.

Abstract

Background & Aims

Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC).

Methods

This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4mm). Performance was assessed using ROC curves corrected by Obuchowski’s method.

Results

Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski’s measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70–73% to 80–83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC’s ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis.

Conclusions

Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.

Source

Editorial: staging liver fibrosis in hepatitis C: a challenge for this decade

Am J Gastroenterol. 2011 Dec;106(12):2121-2. doi: 10.1038/ajg.2011.343

Lai M, Afdhal NH.

Source

Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Abstract

The limitations of and the invasive nature of liver biopsy has spurred extensive interest in the development of non-invasive tests to measure liver fibrosis in patients with chronic hepatitis C. Clinically applicable non-invasive tests, including radiological studies, elastography, and serum markers, all of which perform extremely well in excluding significant disease and diagnosing cirrhosis. FibroScan and acoustic radiation force impulse elastography are two elastography-based tests that show promise. In this new era of increased cure rates with newly Food and Drug Administration-approved drugs and the availability of multiple non-invasive tests of liver fibrosis, we anticipate a decreasing need for liver biopsies in the management of chronic hepatitis C.Am J Gastroenterol 2011; 106:2121-2122; doi:10.1038/ajg.2011.343.

Source

Noninvasive Tests for Fibrosis and Liver Stiffness Predict 5-Year Outcomes of Patients With Chronic Hepatitis C

Gastroenterology
Volume 140, Issue 7 , Pages 1970-1979.e3, June 2011.

Julien Vergniol, Juliette Foucher, Eric Terrebonne, Pierre–Henri Bernard, Brigitte le Bail, Wassil Merrouche, Patrice Couzigou, Victor de Ledinghen

Received 28 November 2010; accepted 18 February 2011. published online 03 March

Abstract

Background & Aims

Liver stiffness can be measured noninvasively to assess liver fibrosis in patients with chronic hepatitis C. In patients with chronic liver diseases, level of fibrosis predicts liver-related complications and survival. We evaluated the abilities of liver stiffness, results from noninvasive tests for fibrosis, and liver biopsy analyses to predict overall survival or survival without liver-related death with a 5-year period.

Methods
In a consecutive cohort of 1457 patients with chronic hepatitis C, we assessed fibrosis and, on the same day, liver stiffness, performed noninvasive tests of fibrosis (FibroTest, the aspartate aminotransferase to platelet ratio index, FIB-4), and analyzed liver biopsy samples. We analyzed data on death, liver-related death, and liver transplantation collected during a 5-year follow-up period.

Results
At 5 years, 77 patients had died (39 liver-related deaths) and 16 patients had undergone liver transplantation. Overall survival was 91.7% and survival without liver-related death was 94.4%. Survival was significantly decreased among patients diagnosed with severe fibrosis, regardless of the noninvasive method of analysis. All methods were able to predict shorter survival times in this large population; liver stiffness and results of FibroTest had higher predictive values. Patient outcomes worsened as liver stiffness and FibroTest values increased. Prognostic values of stiffness (P < .0001) and FibroTest results (P < .0001) remained after they were adjusted for treatment response, patient age, and estimates of necroinflammatory grade.

Conclusions
Noninvasive tests for liver fibrosis (measurement of liver stiffness or FibroTest) can predict 5-year survival of patients with chronic hepatitis C. These tools might help physicians determine prognosis at earlier stages and discuss specific treatments, such as liver transplantation.

Keywords: Survival, Cirrhosis, FibroTest, FibroScan, Hepatitis C

Source

How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy?

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 13–17, January 2011

Laurent Castera 1, Pierre Bedossa 2

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S

Author Information

1 Department of Hepatology, Hôpital St André & Haut Lévêque, Bordeaux University Hospital, Bordeaux, France
2 Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, INSERM, Paris-Diderot University, Paris, France

* Correspondence: Correspondence Laurent Castera, MD, PhD, Service d' Hépatologie, Hǒpital Beaujon, Assistance Publique Hǒpitaux de Paris, 100 Boulevard du Général Leclerc, 92110 Clichy, France Tel: +33 5 57 65 64 39 Fax: +33 5 57 65 64 45 e-mail: laurent.castera@chu-bordeaux.fr

Keywords:
FibroScan; liver biopsy; liver fibrosis; non-invasive; serum biomarkers; transient elastography

Abstract

The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a ‘biological’ approach based on the dosage of serum biomarkers of fibrosis; (ii) a ‘physical’ approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.

Liver fibrosis is a result of excessive extracellular matrix deposition in the liver in response to chronic inflammatory injury triggered by persistent hepatitis C virus in the liver. Hepatic fibrosis is determined by the replication balance between fibrogenesis and fibrosis degradation. When this balance favours fibrogenesis, there is a resulting accumulation of collagen and extracellular matrix, leading eventually to cirrhosis. Liver fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality in patients with hepatitis C virus (HCV) infection (1, 2). Besides the development of antiviral drugs, there are intensive efforts to develop drugs to effectively target the mechanism of fibrogenesis or to eliminate fibrous tissue once it has accumulated in the liver (3). Therefore, the assessment of liver fibrosis is a major issue in the management of patients with chronic HCV infection (4, 5).

Liver biopsy

For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.

However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.

Observer variation is another potential limitation of biopsy that is related to the difference between pathologist's interpretation of the biopsy (6, 9, 10). The use of histopathological scoring systems for the evaluation of fibrosis has limited this drawback and several studies have shown that agreement between pathologists is satisfactory, especially when the staging of fibrosis is performed by specialized liver pathologists (9, 10). Thus, although liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.

Because liver biopsy is invasive, the only serious limitations are the potential adverse effects and complications that have been comprehensively reviewed elsewhere (11). Transient and moderate pain along with anxiety and discomfort are common (12, 13). Severe complications such as haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has been reported occasionally for biopsies in advanced liver diseases, haemorrhagical tumours and in patients with major comorbidities. A biopsy via the transjugular route considerably reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy performed by a trained physician, limiting the number of passes and ultrasound guidance can significantly decrease the risk of complications, thus increasing the safety of biopsy. Nevertheless, a liver biopsy should be performed only after carefully balancing the risks of the procedure with the potential benefits in terms of patient management. Despite these limitations, liver biopsy provides invaluable information that none of the non-invasive markers provide. Although the evaluation of fibrosis is a major decision criterion for hepatologists, fibrosis is only one of the many elementary histopathological features present on liver biopsy. In effect, fibrosis is not an autonomous feature, but scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophical processes. The simultaneous evaluation of necroinflammation (portal tract inflammation, interface hepatitis, lobular inflammation) shows whether fibrosis is the result of a past event that has stabilized or even regressed or is an ongoing process that may continue to worsen. Associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis, can also frequently be detected with biopsy (14).

Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.

Non-invasive methods for the assessment of liver fibrosis

There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).

Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with TE are the aspartate-to-platelet ratio index (APRI) (a free non-patented index) and the FibroTest (21, 22, 23).

The results of TE and serum biomarkers for the diagnosis of significant fibrosis have been shown to be equivalent in patients with chronic hepatitis C infection (24, 25). Indeed, in the largest study to date (n=1307) (25), comparing TE with several patented and non-patented biomarkers (FibroTest, Fibrometre, Hepascore and APRI) and using liver biopsy as a reference, the AUROCs of TE (0.76) did not differ from those of serum biomarkers (0.72–0.78).

In order to increase the diagnostic accuracy of these tests, the sequential combination of biomarkers (26, 27) or the concomitant combination of TE and biomarkers (24, 28, 29) has been proposed. The latter strategy may be more effective for diagnosing significant fibrosis, leading to a reduction in the use of liver biopsy in more than 70% of cases compared with 50% when using biomarkers (APRI and FibroTest) sequentially (30). Another advantage of combining two unrelated methods such as TE and biomarkers rather than two biomarkers is that TE provides a more direct measurement of liver structure than biomarkers and there is no relationship between the applicability of TE and biomarkers such as the FibroTest (28).

For the diagnosis of cirrhosis, the situation is different because TE appears to be the most accurate method compared with currently available biomarkers and routine blood tests, preventing the need for a liver biopsy in around 90% of cases (25, 31). As a result, a combination of both methods does not seem to increase the diagnostic accuracy (30).

Limitations of non-invasive methods

Serum markers

Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).

Transient elastography

Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.

Finally, because the liver is an organ wrapped in an expandable but non-elastic envelope (Glisson's capsula), additional space-occupying tissue abnormalities independent of fibrosis, such as oedema and inflammation, cholestasis and congestion, may interfere with LSM. The risk of overestimating liver stiffness values has been reported in the case of alanine aminotransferase flares in patients with acute viral hepatitis or chronic hepatitis B (38, 39, 40) as well as in cases of extrahepatic cholestasis (41) or congestive heart failure (42).

How to use liver biopsy and non-invasive methods in clinical practice?

A liver biopsy should be performed in the case of comorbidities such as alcoholism or metabolic syndrome when non-invasive methods cannot be used or in any unclear situation such as discordant results of non-invasive tests. Conversely, liver biopsy should not be performed when the clinical diagnosis is obvious (cirrhosis) or when no benefit can be expected from the biopsy for patient management. Although there is no optimal threshold, the longer the specimen, the more accurate the staging will be (43). A 20–25 mm long biopsy is considered optimal although a robust evaluation is often possible on a 15 mm long biopsy. Ideally, the biopsy should be read by an experienced liver pathologist because it decreases the source of variability in the histological interpretation (44).

In naïve patients without comorbidities who are candidates for antiviral treatment, non-invasive tests can be used for the first-line staging of fibrosis. The use of either TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities (45). However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable. For instance, when there is a strong clinical suspicion of cirrhosis, in most cases the use of TE is enough to confirm the diagnosis without a liver biopsy. Conversely, a liver biopsy may be necessary to differentiate between F1 and F2 in genotype 1-infected patients before making a decision on antiviral treatment. In the same way, a liver biopsy may be useful to differentiate between F3 and F4 when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments (46, 47), differentiating between F1 and F2 may not be as important for treatment indications.

When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.

Finally, non-invasive methods can be of interest in the follow-up of untreated patients (48). Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis.

Conclusion and perspectives

There is an urgent need to pursue the development of non-invasive tests in addition to a liver biopsy for the staging of fibrosis. Because of the conditional relationship with biopsy, the development of serum markers will always have obvious limitations. Promising preliminary results suggest that novel alternative imaging techniques such as magnetic resonance elastography, acoustic radiation force impulse imaging or perfusion computed tomography will eventually be refined to reach an acceptable level of accuracy, especially for the evaluation of early and intermediate stages of fibrosis (49–51). These might become less pertinent as antiviral treatments become more efficient, with fewer side effects.

Conflicts of interest

The authors have declared no potential conflicts.

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