Wednesday, December 3, 2014

Noninvasive Alternatives to Assess Liver Fibrosis: Ready for Prime Time?


Noninvasive Alternatives to Assess Liver Fibrosis: Ready for Prime Time?

William F. Balistreri, MD
December 02, 2014

A Common Clinical Scenario

A healthy, asymptomatic 45-year-old woman with newly diagnosed hepatitis C virus (HCV) infection presents for consultation. Her questions relate not only to treatment options but also to her prognosis: "How much damage has the virus caused?" "Is my liver scarred?" She is informed that despite an unremarkable physical examination, the gold standard for determining the extent of fibrosis is liver biopsy. Having researched her diagnosis, the patient expresses her understanding but has valid concerns that this invasive procedure is subject to not only sampling/interpretation error but also, albeit rarely, potentially life-threatening procedure-related complications. She asks, "Is there a noninvasive way to determine the extent of scarring?"

This is an increasingly common clinical scenario owing to various factors.

Awareness of HCV has increased since the recent Centers for Disease Control and Prevention recommendations that everyone in the baby boomer generation undergo a one-time screening test.[1] This is a major advance in public health, but it brings the potential of discovering hundreds of thousands of infected persons.[2] In addition, widespread excitement has been generated by the emergence of new HCV antivirals that offer a high probability of a cure.[3]

Along with these developments in HCV, there is also the reality that the global epidemic of obesity will bring an increasing number of patients with fatty liver disease to our offices.[4]

The flood of patients with liver disease will challenge clinicians to determine the prognosis and eligibility for treatment and to gauge the response to any intervention.

Thus, there is significant interest in the development and validation of noninvasive alternatives to biopsy in the assessment of the extent of liver disease, specifically the degree of fibrosis and the pace of progression. The emergence of these tools will have a significant impact on clinical research as well as the practice of hepatology.
Noninvasive Options for Fibrosis Assessment

The proposed methods of fibrosis assessment in a variety of liver diseases are based on clinical, biochemical, and radiologic variables and are often used in combination. Specifically, the use of serum biomarkers of fibrosis and apoptosis, and several imaging modalities to assess liver stiffness, have been introduced and validated. These noninvasive indices of liver fibrosis offer an enhanced ability to prognosticate and stratify disease, thus improving patient care; they will also inform the development of antifibrotic therapies.[5,6]

Despite this recent progress, questions remain regarding the diagnostic validity, cut-off and threshold values for the degree of fibrosis, cost, and broad applicability of each test, which should be answered with more data obtained through systematic reviews of studies.[7]

Serum Biomarkers

The practical advantages of emerging serum biomarkers include their high applicability and interlaboratory reproducibility, as well as their potential widespread availability. However, these biomarker panels require careful clinical correlation for critical interpretation of results. In addition, serum biomarkers often fail to discriminate adequately between lesser grades of fibrosis. Nevertheless, biomarkers are potentially useful monitoring and prognostic tools, with the ability to predict clinical outcome on the basis of repeated assessment of the ongoing pathophysiologic process of fibrogenesis.

The commonly used biomarkers for the detection of liver fibrosis include simple measures, such as the aspartate aminotransferase-to-platelet ratio index (APRI),[6,8] as well as several marketed products or validated algorithms that assess extracellular matrix turnover (fibrogenesis). These include:

  • FibroMeter™ (Echosens; Paris, France)[9];
  • FibroTest-ActiTest® (Biopredictive; Paris, France); HCV FibroSure® (LabCorp; Burlington, North Carolina)[10,11];
  • HepaScore[12] (also known as FibroScore);
  • Enhanced liver fibrosis (ELF) panel[13,14]; and
  • Fibrosis-4 (FIB-4) index.[15,16]
Each is derived from a panel of analytes that have been shown to predict the process or extent of fibrogenesis; please consult the cited references for specific details.

To varying degrees, these tests have achieved acceptance. Vergniol and colleagues[15] reported the value of several of these noninvasive tests in monitoring patients with chronic HCV infection and in predicting their outcome over a 3-year evolution of liver fibrosis. A meta-analysis by Xiao and colleagues[16] suggested that APRI and FIB-4 can identify hepatitis B virus (HBV)-related fibrosis with moderate sensitivity and accuracy.

The FibroTest was shown to correlate with survival and to have a similar 5-year prognostic value to that of liver biopsy in patients with a variety of liver diseases, such as chronic HBV or HCV and alcoholic liver disease.[17] Vallet-Pichard and colleagues[18] validated the simple, inexpensive FIB-4 index, which combines standard biochemical values (platelets, alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and age, as an accurate method for assessing liver fibrosis, concordant with FibroTest results.

Imaging Techniques
Transient Elastography
Over the past 5 years, transient elastography (TE) has become accepted as a noninvasive marker of fibrosis. TE, which relies on sonic detection of liver stiffness to predict hepatic fibrosis, has been validated in patients with chronic hepatitis.[19] TE methodology offers several distinct advantages: a brief procedure time, immediate availability of results, and the option of performing the procedure in real time at the bedside or in the outpatient clinic.

TE has some limitations. As with any tool, the results are often in the hands of the user. Interpretation must be correlated with the clinical context and other test results (biochemical, radiologic, and endoscopic).[20] In addition, liver stiffness may be overestimated in the presence of confounding factors, such as obesity, extrahepatic cholestasis, and congestive heart failure.[21] Appropriate cut-off values for diagnosing fibrosis and distinguishing cirrhosis must be further defined for each assay.[22] Numerous published studies, some of which are summarized here, have addressed the rationale, reliability, and limitations of this technique.

Wong and colleagues examined the accuracy of TE as measured by FibroScan® (Echosens; Paris, France) among patients with nonalcoholic fatty liver disease (NAFLD).[23]Liver stiffness increased significantly with fibrosis. TE was highly accurate for detecting significant/advanced fibrosis and cirrhosis. Its accuracy was not affected by body mass index (BMI) or steatosis grade and was similar to that of other clinical and biochemical noninvasive measures: APRI, FIB-4, NAFLD fibrosis score, and BARD score (derived from BMI, AST/ALT ratio, and the presence of diabetes).

Degos and colleagues[24] compared the accuracy of TE, assessed using FibroScan, with that of serum biomarkers in the prediction of significant biopsy-proven fibrosis in patients with chronic viral hepatitis. The overall accuracy of FibroScan was significantly higher than that of biomarkers.

Pang and colleagues[17] tested the ability of liver stiffness measurement by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. They used Cox regression to determine the independent association between liver stiffness and hepatic complications or death. After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications. TE may help estimate prognosis and guide management of patients with chronic liver disease.

Significant fibrosis may be present in patients with NAFLD despite normal liver tests and ultrasonography.[5,25] Liver stiffness measurement by TE proved to be useful and specific to screen for cirrhosis in the general population and to detect undiagnosed chronic liver disease in apparently healthy persons.[26,27] Liver stiffness values in the general population were found to be influenced independently by sex, BMI, and the metabolic syndrome.[28,29]

Liver stiffness values vary after a test meal, presumably owing to adaptation of the hepatic microcirculation to increased portal blood flow; postprandial hyperemia is associated with a greater increase in portal pressure in patients with cirrhosis.[30,31] Arena and colleagues[32] characterized the "confounding" increase in liver stiffness after a standardized meal in patients with chronic HCV infection at different stages of evolution of the process of fibrogenesis. They detected evidence of the confounding effect of a meal on the accuracy of liver stiffness measurements for the prediction of fibrosis stage in patients with chronic HCV hepatitis and suggested that patients should fast for 120 minutes before TE is performed.

Magnetic Resonance Elastography

Several MRI techniques have also been proposed for assessing hepatic fibrosis. The most common approach is magnetic resonance elastography (MRE).[5,33-37] MRE quantitatively measures and visualizes propagating acoustic shear waves that progress through liver tissue.[5,38] This test has been of value in the assessment of chronic liver disease in children, a population in which determination of the stage of liver injury is especially limited by lack of validated noninvasive biomarkers of histologic severity. In a case series of 35 children with chronic liver disease, including severely obese children, Xanthakos and colleagues[38] demonstrated that MRE is feasible and accurate in detecting significant hepatic fibrosis.

Acoustic radiation force impulse (ARFI) imaging is a promising method that involves the mechanical excitation of tissue using short-duration acoustic pulses. The ARFI method can be embedded into a conventional ultrasonographic scanner to allow formal examination of the hepatic parenchyma as well.[7] Several published studies have addressed the rationale, reliability, and limitations of this technique; preliminary results suggest very similar performance to that of TE, although further validation is warranted.

Leung and colleagues[6] documented the utility of shear-wave (SW) elastography for assessing liver fibrosis in patients with chronic hepatitis B and compared its performance with that of TE. SW elastography of the liver, SW elastography of the spleen, and TE of the liver were compared and correlated with biopsy-derived fibrosis scores. SW elastography of the liver showed significantly higher accuracy than TE of the liver and SW elastography of the spleen in all fibrosis stages. SW elastography of the liver had a higher success rate than TE of the liver (98.9% vs 89.6%). Real-time SW elastography was also shown to be accurate for assessing liver fibrosis in patients with chronic hepatitis C.[39]

Spleen stiffness as a predictive model. Takuma and colleagues[40] also documented the prognostic value of spleen stiffness, as detected by ultrasonography (ARFI imaging), in the evaluation of patients with cirrhosis, specifically differentiating patients at low risk for decompensation from those at high risk. Similar results were documented in other centers and in a pediatric population.[41,42]
Not the End of Liver Biopsy Yet

It seems that these noninvasive techniques have had an impact by decreasing the number of liver biopsies performed. In addition, such modalities as MRE have given us a "number" to share with the patient—one that reflects the degree of liver fibrosis.

However, the story is incomplete. More data are needed, including studies that compare strategies using TE, MRE, ARFI, or biomarkers (perhaps in combination) in various populations. Finally, the cost-effectiveness of each screening/monitoring strategy must be further evaluated before broad implementation can be recommended.

Source - Medscape

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