Coverage Policy Manual
Policy #: 2016007
Category: Radiology
Initiated: March 2016
Last Review: May 2024
  Noninvasive Imaging Technologies for Evaluation of Hepatic Fibrosis and Other Tissues (Elastography)

Description:
The diagnosis of non-neoplastic liver disease is often made from needle biopsy samples. In addition to establishing a disease etiology, liver biopsy can determine the degree of inflammation present and can stage the degree of fibrosis. The degree of inflammation and fibrosis may be assessed by different scoring schemes. Most of these scoring schemes grade inflammation from 0 to 4 (0 = no or minimal inflammation, 4 = severe) and fibrosis from 0 to 4 (0 = no fibrosis, 4 = cirrhosis). There are several limitations to liver biopsy, including its invasive nature, small tissue sample size, and subjective grading system. Regarding small tissue sample size, liver fibrosis can be patchy and thus missed on a biopsy sample, which includes only 0.002% of the liver tissue. A noninvasive alternative to liver biopsy would be
particularly helpful, both to initially assess patients and then as a monitoring tool to assess response to therapy.
 
Noninvasive Imaging Technologies
Noninvasive imaging technologies to detect liver fibrosis or cirrhosis among patients with chronic liver disease are also being evaluated as an alternative to liver biopsy. The noninvasive imaging technologies include transient elastography (eg, FibroScan®), magnetic resonance elastography (MRE), ARFI (eg, Acuson S2000™), and real-time tissue elastography (RTE; eg, HI VISION Preirus). Noninvasive imaging tests have been used in combination with multianalyte serum tests such as FibroTest or FibroSURE with FibroScan.
 
Transient Elastography
Transient elastography (FibroScan®) uses a mechanical vibrator to produce mild amplitude and lowfrequency (50 Hz) waves, inducing an elastic shear wave that propagates throughout the liver. US tracks the wave, measuring its speed, which correlates with liver stiffness. Increases in liver fibrosis also increase liver stiffness and resistance of liver blood flow. Transient elastography does not perform as well in patients with ascites, higher body mass index, or narrow intercostal margins. Although FibroScan may be used to measure fibrosis, unlike liver biopsy, it does not provide information on necroinflammatory activity and steatosis, nor is it accurate during acute hepatitis or hepatitis exacerbations.
 
Acoustic Radiation Force Impulse Imaging
ARFI uses an US probe to produce an acoustic “push” pulse, which generates shear waves that propagate in tissue to assess liver stiffness. ARFI elastography evaluates the wave propagation speed to assess liver stiffness. The faster the shear wave speed, the harder the object. ARFI technologies include Virtual Touch™ Quantification and Siemens Acuson S2000™ system. ARFI elastography can be performed at the same time as a liver sonographic evaluation, even in patients with a significant amount of ascites.
  
Magnetic Resonance Elastography
MRE uses a driver to generate 60-Hz mechanical waves on the patient’s chest well. The MRI equipment creates elastograms by processing the acquired images of propagating shear waves in the liver using an inversion algorithm. These elastograms represent the shear stiffness as a pixel value in kilopascals. MRE has several advantages over US elastography, including: (1) analyzing larger liver volumes; (2) analyzing liver volumes of obese patients or patients with ascites; and (3) precise analysis of viscoelasticity using a 3-dimensional displacement vector.
 
Real-Time Tissue Elastography
RTE is a type of strain elastography which uses a combined autocorrelation method to measure tissue strain caused by manual compression or a person’s heartbeat. The relative tissue strain is displayed on conventional color B mode US images in real time. Hitachi manufacturers the RTE devices, including one called HI VISION Preirus. The challenge is to identify a region of interest while avoiding areas likely to introduce artifacts, such as large blood vessels, the area near the ribs, and the surface of the liver. Areas of low strain increase as fibrosis progresses and strain distribution becomes more complex. Various subjective and quantitative methods have been developed to evaluate the results. RTE can be performed in patients with ascites or inflammation. This technology does not perform as well in severely obese
individuals.
 
Multiparametric Magnetic Resonance Imaging
Multiparametric MRI combines proton density fat-fraction, T2*, and T1 mapping. Proton density fat-fraction provides an assessment of hepatic fat content and can be used to determine the grade of liver steatosis. T1 relaxation times are used to assess increases in extracellular fluid, which correlates with the extent of fibrosis and inflammation of the liver. Hepatic iron quantification is measured through T2* relaxation times as T1 relaxation times are decreased by excess iron in the liver tissue. LiverMultiScan® uses a clinical algorithm that accounts for an iron-corrected T1 value, based on the T2* relaxation time, and proton density fat-fraction to assess the presence of fat, inflammation, and fibrosis.
 
 
REGULATORY STATUS
In 2008, Acuson S2000™ (Siemens AG), which provides ARFI imaging, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process (K072786)(K123622).
 
In 2009, AIXPLORER® Ultrasound System (SuperSonic Imagine), which provides shear wave elastography, was cleared for marketing by the FDA through the 510(k) process (K091970).
 
In 2010, Hitachi HI VISION Preirus Diagnostic Ultrasound Scantier (Hitachi Medical Systems America), which provides shear wave elastography, was cleared for marketing by FDA through the 510(k) process (K093466).
 
In 2013, FibroScan® (EchoSens), which uses transient elastography, was cleared for marketing by the FDA through the 510(k) process (K123806).
 
In June 2015, LiverMultiScan (Perspectum), which is a magnetic resonance diagnostic device software application, was cleared for marketing by the FDA through the 510(k) process (K143020).
 
In February 2017, ElastQ Imaging shear wave elastography (Royal Phillips) was cleared for marketing by the FDA through the 510(k) process (K163120).
 
FDA product code: IYO.
 
Coding
Effective in 2015, there is a specific CPT code for elastography:
 
91200 Liver elastography, mechanically induced shear wave (eg, vibration), without imaging, with interpretation and report
 
This policy does not address standard imaging with ultrasound or MRI.
 

Policy/
Coverage:
Effective January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of transient elastography (Fibroscan®) and acoustic radiation force impulse imaging (ARFI; eg, Acuson S2000) meets member benefit certificate primary coverage criteria and is covered twice per year when used in conjunction with simple biomarkers (e.g., Fib4 and/or APRI) in the evaluation of Hepatitis C as an alternative to liver biopsy.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of other noninvasive imaging, including magnetic resonance elastography, real-time tissue elastography, or FibroSURE multianalyte assay for the evaluation or monitoring of patients with chronic liver disease or any other medical condition does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of other noninvasive imaging, including magnetic resonance elastography, real-time tissue elastography, or FibroSURE multianalyte assay is considered investigational and/or not medically necessary for the evaluation or monitoring of patients with chronic liver disease or any other medical condition.  Investigational services and services that are not medically necessary are specific contract exclusions in most member benefit certificates of coverage.
 
Effective May 2017 through December 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
The use of transient elastography (Fibroscan®) and acoustic radiation force impulse imaging (ARFI;
eg, Acuson S2000) meets member benefit certificate primary coverage criteria and is covered twice per year when used in conjunction with simple biomarkers (e.g., Fib4 and/or APRI) in the evaluation of Hepatitis C as an alternative to liver biopsy.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
The use of other noninvasive imaging, including magnetic resonance elastography, real-time tissue elastography, or FibroSURE multianalyte assay for the evaluation or monitoring of patients with chronic liver disease does not meet member benefit certificate primary coverage criteria.
 
For members with contracts with primary coverage criteria, the use of other noninvasive imaging, including magnetic resonance elastography, real-time tissue elastography, or FibroSURE multianalyte assay is considered investigational for the evaluation or monitoring of patients with chronic liver disease. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to May 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of transient elastography (Fibroscan®) and acoustic radiation force impulse imaging (ARFI; eg, Acuson S2000) meets member benefit certificate primary coverage criteria and is covered twice per year when used in conjunction with simple biomarkers (e.g., Fib4 and/or APRI) in the evaluation of Hepatitis C as an alternative to liver biopsy.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of other noninvasive imaging, including magnetic resonance elastography or real-time tissue elastography, for the evaluation or monitoring of patients with chronic liver disease does not meet member benefit certificate primary coverage criteria.
 
For members with contracts with primary coverage criteria, the use of other noninvasive imaging, including magnetic resonance elastography or real-time tissue elastography, is considered investigational for the evaluation or monitoring of patients with chronic liver disease. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO APRIL 2016
 
The use of noninvasive imaging, including but not limited to transient elastography (eg, FibroScan), magnetic resonance elastography, acoustic radiation force impulse imaging (ARFI; eg, Acuson S2000), or real-time tissue elastography, for the evaluation or monitoring of patients with chronic liver disease does not meet member benefit certificate primary coverage criteria.
 
For members with contracts with primary coverage criteria, the use of noninvasive imaging, including but not limited to transient elastography (eg, FibroScan), magnetic resonance elastography, acoustic radiation force impulse imaging (ARFI; eg, Acuson S2000), or real-time tissue elastography, is considered investigational for the evaluation or monitoring of patients with chronic liver disease. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
A 2014 Blue Cross Blue Shield Association Technology Evaluation Center (TEC) Assessment (TEC, 2014) evaluated the use of noninvasive imaging to detect liver fibrosis or cirrhosis among patients with chronic hepatitis C. The noninvasive imaging types included transient elastography (eg, FibroScan®), magnetic resonance elastography (MRE), acoustic radiation force impulse imaging (ARFI; eg, Acuson S2000™), and real-time tissue elastography (RTE; eg, HI VISION Preirus). The TEC Assessment concluded evidence is insufficient to permit conclusions on the effect of noninvasive imaging to detect liver fibrosis or cirrhosis in patients with chronic hepatitis C and any net improvement on health outcomes cannot be established.
 
Transient Elastography
The TEC Assessment (TEC, 2014) found extensive literature on the use of transient elastography to gauge liver fibrosis and cirrhosis, but the body of evidence has a number of limitations. Included in the TEC Assessment were 3 meta-analyses on the use of FibroScan to identify fibrosis or cirrhosis in adult patients with chronic hepatitis C (Steadman, 2013; Tsochatzis, 2011; Bota, 2013). All of the diagnostic studies had a medium risk of bias. The cut-points in kilopascals to distinguish between stages of fibrosis and cirrhosis using FibroScan varied across studies, and some studies provided results for multiple cutpoints. In general, the test performance characteristics, such as AUROC, improved as one moved from significant fibrosis to bridging fibrosis and cirrhosis to cirrhosis. The statistical significance of these changes was seldom reported, although 95% CIs were provided. Several studies reported likelihood ratios. The positive likelihood ratio increased from >F2 to >F3 to F4 and was usually larger than 5. The negative likelihood ratio was less than 0.2 in 1 of 3 cases for >F3 and in 2 of 3 cases for F4. The TEC Assessment concluded evidence on transient elastography is insufficient to determine its accuracy in identifying significant fibrosis, bridging fibrosis and cirrhosis, and cirrhosis and its effects on health outcomes. Therefore, the available evidence is insufficient to permit conclusion on the effect on health outcomes of transient elastography to detect liver fibrosis or cirrhosis among patients with chronic hepatitis C.
 
ARFI Imaging
The TEC Assessment found limited evidence on ARFI (TEC, 2014). In a meta-analysis, Bota et al compared transient elastography with ARFI elastography, with liver biopsy as the reference standard (Bota, 2013). This metaanalysis did not reveal major differences in accuracy between transient elastography and ARFI elastography. There was no indication of major publication bias. In a meta-analysis on ARFI, an analysis of 6 studies was reported on including 380 patients with chronic hepatitis C (Friedrich-Rust, 2012). Using random-effects estimators and individual-level data, the area under the ROC curve was 0.88 (95% CI, 0.83 to 0.93) for F2, 0.90 (95% CI, 0.84 to 0.97) for F3, and 0.92 (95% CI, 0.87 to 0.98) for F4. There was significant heterogeneity among the studies for F3 and F4. The TEC Assessment concluded the paucity of the evidence on ARFI precludes any conclusion about its accuracy relative to liver biopsy or transient elastography or about ARFI alone versus liver biopsy, or about its effects on health outcomes.
 
Magnetic Resonance Elastography
The TEC Assessment found limited evidence on MRE.33 One retrospective study assessed the performance of contrast-enhanced MRE among 114 hepatitis C patients who had had a liver biopsy within the last 2 months (Ichikawa, 2012). There were only 3 true negatives in the F1 category. It appears that MRE is most sensitive in detecting cirrhosis (F4), but no p values are reported comparing sensitivity across fibrosis categories. The limited evidence on MRE precludes any conclusion about its accuracy relative to liver biopsy or other types of noninvasive imaging or about its effects on health outcomes.
 
Real-Time Tissue Elastography
The TEC Assessment found limited evidence on RTE.33 One study on RTE of 138 patients with hepatitis C reported transient elastography performed significantly better than RTE for all stages of fibrosis (F2, F3, F4) (Ferraioli, 2012). The positive likelihood ratio for F2 was 8.36 for transient elastography and 2.04 for RTE. The negative likelihood ratio for F2 was 0.31 for transient elastography and 0.31 for RTE. The paucity of the evidence on RTE precludes any conclusion about its accuracy relative to liver biopsy or other types of noninvasive imaging, or about its effects on health outcomes.
 
Noninvasive Imaging in Hepatitis B
Steadman et al reported on the performance of transient elastography in various liver diseases, including hepatitis B.34 There were differences in sensitivity for detecting cirrhosis between patients with hepatitis B (0.67; 95% CI, 0.57 to 0.75) and hepatitis C (0.85; 95% CI, 0.77 to 0.91), and the 95% Cis did not overlap. However, the test characteristics varied by disease, differed by stage (ie, F2, F3, F4) and by disease comparison. Furthermore, a larger proportion of studies reported on hepatitis C than on other diseases. Studies also reported different cutpoints for significant fibrosis (F2) or cirrhosis (F4), depending on underlying disease (Stebbing, 2010). No significant differences in accuracy were reported for transient elastography between chronic hepatitis B and chronic hepatitis C in the meta-analysis by Tsochatzis et al (Tsochatzis, 2011). In other words, the evidence on the degree to which FibroScan performs similarly across different disease states appears to be inconsistent. Evidence on other noninvasive imaging for hepatitis B is limited, therefore, conclusion on accuracy in hepatitis B and effects on health outcomes cannot be determined.
 
Combined Use of Multianalyte Assays and Noninvasive Imaging
The combined use of multianalyte assays with algorithmic analyses and noninvasive imaging has been evaluated to determine whether this adds incremental accuracy for the evaluation or monitoring of liver fibrosis in patients with chronic liver disease. Few studies have evaluated the incremental accuracy of the combined use of tests. Therefore, there is insufficient evidence to determine the incremental benefit of combining multianalyte assays with noninvasive imaging and its effects on health outcomes cannot be determined.
 
2017 Update
A literature search conducted through March 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The systematic review by Crossan and colleagues was performed for the Health Technology Assessment (HTA) program of the National Institute for Health Research (Crossan, 2015). The first objective of the review was to determine the diagnostic accuracy of different noninvasive liver tests compared to liver biopsy in the diagnosis and monitoring of liver fibrosis and cirrhosis in patients with hepatitis C virus (HCV), hepatitis B virus (HBV), nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Three hundred two publications and presentations from 1998 to April 2012 were included. Patients with HCV were the most common population included in the studies while patients with ALD were the least common. FibroScan and FibroTest were the most commonly assessed tests across liver diseases. APRI was also widely assessed in HBV and HCV but not in NAFLD or ALD. Estimates of diagnostic accuracy from Crossan for each test by disease are discussed in more detail in the following sections. Briefly, for diagnosing significant fibrosis (stage F2) in HCV, the summary sensitivities and specificities were: FibroScan, 79% and 83%; FibroTest, 68% and 72%; APRI (low cutoff), 82% and 57%; ARFI, 85% and 89%; HepaScore, 73% and 73%, FIBROSpect II, 78% and 71%; and FibroMeter, 79% and 73%, respectively. For diagnosing advanced fibrosis in HBV, the summary sensitivities and specificities were: FibroScan, 71% and 84%; FibroTest, 66% and 80%, respectively. There are no established or validated cutoffs for fibrosis stages across the diseases for most tests. For FibroTest, established cutoffs exist but were used inconsistently across studies. Failures of the test or reference standard were frequently not captured in analyses. The populations included in the studies were generally from tertiary care settings who have more advanced disease than the general population, which would overestimate the prevalence of the disease and diagnostic accuracy. These issues likely cause overestimates of sensitivities and specificities. The quality of the studies was generally rated as poor, with only 1.6% receiving a high quality rating.
 
Houot and colleagues reported on a systematic review funded by BioPredictive, the manufacturer of FibroTest (Houot, 2016). Reviewers included 71 studies published between January 2002 to February 2014 with over 12,000 participants with HCV and HBV comparing the diagnostic accuracy of FibroTest, FibroScan, APRI, and FIB4 index. Reviewers included studies that directly compared the tests and calculated median differences in the AUROC using Bayesian methods. There was no evaluation of the methodologic quality of the included studies. The Bayesian difference in AUROC curve for significant fibrosis (stage F2) between FibroTest and FibroScan was based on 15 studies and estimated to be 0.06 (95% credible interval [CrI], 0.02 to 0.09) favoring FibroTest. The difference in AUROC curve for cirrhosis for FibroTest versus FibroScan was based on 13 studies and estimated to be 0.00 (95% CrI, 0.04 to 0.04). The difference for advanced fibrosis between FibroTest and APRI was based on 21 studies and estimated to be 0.05 (95% CrI, 0.03 to 0.07); for cirrhosis, it was based on 14 studies and estimated to be 0.05 (95% CrI, 0.00 to 0.11), both favoring FibroTest.
 
 
Hepatitis C Virus
Effects on Patient Outcomes
 
The effect on patient outcomes of a test depends on a demonstration that the test can be used to improve patient management. The primary benefit of the FibroSURE (FibroTest) for HCV is the ability to avoid liver biopsy in patients without significant fibrosis. Thus, empiric data are needed that demonstrate that the FibroSURE test impacts clinician decision making on whether a biopsy should be performed and that the net effect is to reduce the overall number of biopsies while achieving similar clinical outcomes. There are currently no such published studies to demonstrate effect on patient outcomes. However, FibroTest has been used as an alternative to biopsy to establish trial eligibility in terms of fibrosis or cirrhosis in several trials (ION-1,-3; VALENCE; ASTRAL-2, -3, -4) that established efficacy of HCV treatments (Afdhal, 2014-Apr; Afdhal, 2014-May; Curry 2015; Foster, 2015; Kowdley, 2014; Zeuzem, 2014). For example, in the ASTRAL-2 and -3 trials, cirrhosis could be defined by liver biopsy, FibroScan, or FibroTest score of more than 0.75 and an APRI of more than 2.
 
These tests also need to be adequately compared with other noninvasive tests of fibrosis to determine their comparative efficacy. In particular, the proprietary, algorithmic tests should demonstrate superiority to other readily available, nonproprietary scoring systems to demonstrate that the tests improve health outcomes.
 
The test also has potential effect on patient outcomes as a means to follow response to therapy. In this case, evidence needs to demonstrate that use of the test for response to therapy impacts decision making and that these changes in management decisions lead to improved outcomes. It is not clear whether the HCV FibroSURE could be used as an interval test in patients receiving therapy to determine whether an additional liver biopsy was necessary.
 
Transient Elastography (FibroScan)
 
Technical Performance
Fraquelli and colleagues cited high intra- and inter-observer agreement for transient elastography results of 96% to 98% and 89% to 98%, respectively (Fraquelli, 2007). In a retrospective study of 38,464 Chinese patients with HBV, HCV, liver cirrhosis, ALD, autoimmune liver disease, and hepatocellular carcinoma, Ji and colleagues  examined clinical and biologic factors associated with TE reliability (Ji2014)  Trained operators performed 10 transient elastography measurements per patient in the target area. “Unsuccessful” results were those that obtained no values after at least 10 shots. “Unreliable” results were those for which the interquartile range divided by the median was greater than 0.30 or if the median was greater than 7.1 kilopascals (kPa). Approximately 2.5% of examinations were unsuccessful and 0.85% were unreliable. Success and reliability were independently associated with BMI, female sex, age, and size of intercostal spaces. Castera and colleagues estimated that no valid shots could be obtained in 3% of examinations while 15% of examinations produced unreliable results in a study of 13,369 examinations over a 5-year period (Castera, 2010). Success and reliability were associated with BMI, operator experience, age, female sex, hypertension, type 2 diabetes, and waist circumference.
 
Diagnostic Accuracy
There is extensive literature on the use of transient elastography to gauge liver fibrosis and cirrhosis, but the body of evidence has a number of limitations.
 
Brener and colleagues performed an HTA summarizing many of the systematic reviews below (Brener, 2015). The HTA focused on reviews of the diagnostic accuracy and effect on patient outcomes of transient elastography for liver fibrosis in patients with HCV, HBV, NAFLD, ALD, or cholestatic diseases.
 
Acoustic Radiation Force Impulse Imaging
 
Technical Performance
Piscaglia  and colleagues demonstrated that the interoperator reproducibility of ARFI was high (r=0.874) in a study of 133 patients with chronic liver disease, and the method was feasible for all patients enrolled (Pascaglia, 2011).  Other measures of technical performance were not found.
 
Magnetic Resonance Elastography
 
Technical Performance
A phase 1 study examined the interobserver agreement between 2 pathologists who assessed with MRE using biopsy results from103 patients with chronic hepatitis B and C (Runge, 2014).The intraclass correlation coefficient (ICC) was very high at 0.99 (95% CI, 0.98 to 1.00). For the same patients, the ICC for these 2 pathologists using Metavir was 0.91 (95% CI, 0.86 to 0.94; difference with 23 MRE, p<0.001). In a second phase 1 study of 110 patients and 10 normative volunteers, the ICC for 2 raters was 0.993 for MRE. The absolute differences in elasticity assigned by the 2 raters were less than 0.8 kPa for more than 95% of the subjects. Twenty-one patients had also undergone liver biopsy. Shi and colleagues demonstrated that, in 22 healthy volunteers liver, MRE had good short and mid-term (within 6 mo) repeatability (Shi, 2014). Venkateshand colleagues showed that liver stiffness measurements on MRE performed 4 to 6 weeks apart in a study of 41 healthy Asian volunteers had an ICC of 0.9 (95% CI, 0.78 to 0.96) and a within-subject coefficient of variation of 2.2% to 11.4% (Venkateshand, 2014). Yin and colleagues retrospectively analyzed 1377 consecutive MRE examinations performed between 2007 and 2010 for patients with various chronic liver diseases (Yin, 2016). MRE had a success rate of 94% and highly reproducible measurements (r=0.972, p<0.001). BMI was not associated with success.
 
Real-Time Tissue Elastography (HI VISION 15 Preirus)
 
Technical Performance
In a study of 70 hospitalized patients with HCV, RTE was performed at 4 liver locations by 2 independent observers. The elastic ratio (ratio of the value in the intrahepatic venous small vessels divided by the value in the hepatic parenchyma) was highly correlated between the 2 examiners (R2=0.869, p<.001) and consistent across liver locations (κ=0.835, ICC=0.966) (Koizumi, 2011). Other measures of technical performance were not found.
 
Diagnostic Accuracy
Hong and colleagues reported results of a meta-analysis RTE for staging fibrosis in multiple diseases (Hong, 2014). Thirteen studies (total N=1347 patients) published between April 2000 and April 2014 that used liver biopsy or transient elastography as the reference standard were included. Different quantitative methods were used to measure liver stiffness: Liver Fibrosis Index (LFI), Elasticity Index (EI), elastic ratio 1 (ER1), and elastic ratio 2 (ER2) in the included studies. For predicting significant fibrosis (stage F2), the pooled sensitivities for LFI and ER1 were 78% (95% CI, 70% to 84%) and 86% (95% CI, 80% to 90%), respectively. The specificities were 63% (95% CI, 46% to 78%) and 89% (95% CI, 83% to 94% and the  AUROCs were 0.79 (95% CI, 0.75 to 0.82) and 0.94 (95% CI, 0.92 to 0.96) ,respectively. For predicting cirrhosis (stage F4), the pooled sensitivities of LFI, ER1, and ER2 were 79% (95% CI, 61% to 91%), 96% (95% CI, 87% to 99%), and 79% (95% CI, 61% to 91%), respectively. The specificities were 88% (95% CI, 81% to 93%) for LFI, 89% (95% CI, 83% to 93%) for ER1, and 88% (95% CI, 81% to 93%) for ER2, and the AUROCs were 0.85 (95% CI, 0.81 to 0.87), 0.93 (95% CI, 0.94 to 0.98), and 0.92 (95% CI NR), respectively. Pooled estimates for EI were not performed due to insufficient data.
 
Kobayashi and colleagues published results of a meta-analysis of RTE for staging liver fibrosis (Kobayashi, 2015). They included 15 studies (total N=1626 patients) published through December 2013, including patients with multiple liver diseases and healthy adults. A bivariate random-effects model was used to estimate summary sensitivity and specificity. The summary AUROC, sensitivity, and specificity were 0.69 (precision NR), 79% (95% CI, 75% to 83%) and 76% (95% CI, 68% to 82%), respectively, for detection of significant fibrosis (stage F2) and 0.72 (precision NR), 74% (95% CI, 63% to 82%), and 84% (95% CI, 79% to 88%) for detection of cirrhosis. Reviewers found evidence of heterogeneity due to differences in study populations, scoring methods, and cutoffs for positivity. They also found evidence of publication bias based on funnel plot asymmetry.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Practice Guidelines and Position Statements
 
American Gastroenterological Association et al
The practice guidelines on the diagnosis and management of nonalcoholic fatty liver disease (NAFLD), developed by the American Gastroenterological Association, the American Association for the Study of Liver Diseases, and the American College of Gastroenterology (2018) stated that “NFS [NAFLD fibrosis score] or FIB-4 [Fibrosis-4] index are clinically useful tools for identifying NAFLD patients with higher likelihood of having bridging fibrosis (stage 3) or cirrhosis (stage 4) (Chalasani, 2018).” It also cited VCTE [vibration-controlled transient elastography] and MRE [magnetic resonance elastography] as “clinically useful tools for identifying advanced fibrosis in patients with NAFLD.”
 
American Association for the Study of Liver Diseases and Infectious Diseases Society of America
The American Association for the Study of Liver Diseases and Infectious Diseases Society of America (2018) guidelines for testing, managing, and treating hepatitis C virus (HCV) recommended that, for counseling and pretreatment assessment purposes, the following should be completed:
 
“Evaluation for advanced fibrosis using liver biopsy, imaging, and/or noninvasive markers is recommended in all persons with HCV infection to facilitate an appropriate decision regarding HCV treatment strategy and determine the need for initiating additional measures for the management of cirrhosis (eg, hepatocellular carcinoma screening).
 
Rating: Class I, Level A [evidence and/or general agreement; data derived from multiple randomized trials, or meta-analyses] (American Association for the Study of Liver Diseases, 2018)”
 
The guidelines noted that there are several noninvasive tests to stage the degree of fibrosis in patients with hepatitis C. Tests included indirect serum biomarkers, direct serum biomarkers, and vibration-controlled liver elastography. The guidelines asserted that no single method is recognized to have high accuracy alone and careful interpretation of these tests is required.
 
 2020 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Lin et al conducted a systematic review assessing the diagnostic accuracy of Acoustic Radiation Force Impulse Imaging (ARFI) through April of 2019 (Lin, 2020). 29 studies were included. The population included individuals with non-viral liver disease. 23 studies included individuals with significant fibrosis and 14 included individuals with cirrhosis. The pooled sensitivity and specificity were 0.79 (0.73, 0.83) and 0.81 (0.75, 0.86), with AUROC 0.87 (0.83, 0.89) for the staging of significant fibrosis.  The pooled sensitivity and specificity were 89% (79% to 95%) and 89% (85% to 92%), with AUROC 0.94 (0.92 to 0.96) for cirrhosis. Based on the review, ARFI exerted satisfactory diagnostic performance in staging non-viral hepatic fibrosis, especially severe fibrosis and cirrhosis.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Castellana et al conducted a meta-analytic head-to-head comparison between FIB-4 and NFS and found no significant differences regarding relative diagnostic OR, positive likelihood ratio, and negative likelihood ratio (Castellana, 2021). FIB-4 was associated with fewer indeterminate findings compared to NFS. Mozes et al found that FibroScan, a transient elastography test, outperformed all of the serum-based tests (Mozes, 2021).
 
Younossi et al evaluated the diagnostic value of ELF to assess liver fibrosis in patients with NAFLD (Younossi, 2021). This was a retrospective, cross-sectional study including 829 patients; 462 had transient elastography data and 463 had liver biopsy data. A significant increase in ELF scores was correlated in patients with advanced fibrosis by biopsy or transient elastography. The AUROC for ELF for identifying fibrosis was 0.81 (95% CI, 0.77 to 0.85) with biopsy as the reference standard and 0.79 (95% CI, 0.75 to 0.82) with transient elastography as the reference standard. Predictive combinations of ELF and FIB-4 scores were additionally evaluated. For ELF score 7.2 with a FIB-4 score 0.74, the sensitivity and NPV were 92.5% (95% CI, 87.4% to 97.5%) and 95.1% (95% CI, 91.8% to 98.4%), respectively, for ruling out fibrosis. For ELF score 9.8 with a FIB-4 score 2.9, the specificity and PPV were 99.7% (95% CI, 99.1% to 100%) and 95.0% (95% CI, 85.5% to 100%), respectively, for ruling in fibrosis.
 
Liu et al conducted a meta-analysis to evaluate the use of noninvasive scoring systems and histological scores to predict clinical outcomes in patients with NAFLD (Liu, 2021). Nineteen prospective or retrospective observational trials were included the study. The cutoff points of each scoring system were the same in each included study. There were 4, 3, and 3 studies included in the meta-analysis for assessing the predictive value of NFS, FIB-4, and APRI, respectively, for all-cause mortality. Both NFS-high versus NFS-low (thresholds, -1.455 and 0.676; pooled hazard [HR], 1.44; 95% CI, 1.05 to 1.96) and FIB-4-intermediate versus FIB-4-low (thresholds, 1.30 and 2.67; pooled HR, 1.55; 95% CI, 1.16 to 2.06) demonstrated statistical significance for predicting all-cause mortality. APRI was not predictive for all-cause mortality.
 
A few studies have evaluated the diagnostic accuracy of multiparametric MRI, which incorporates assessment of proton density fatfraction, T2*, and T1 mapping to characterize liver fat, iron, fibrosis, and inflammation. Generally, technical failures were less common with MRI than transient elastography (Beyer, 2021; Imajo, 2021; McDonald, 2018).
 
Jayaswal et al compared the prognostic value of MRI cT1 measurements, transient elastography, and multianalyte serum assays in a cohort of 197 patients with compensated chronic liver disease (Jayaswal, 2020). Patients who were referred for a clinically indicated liver biopsy, or with a known diagnosis of liver cirrhosis, were eligible. At baseline, patients underwent multiparametric MRI scans, transient elastography, and blood tests. Additionally, all patients received a liver biopsy and had their fibrosis rated on the Ishak scale; results of the biopsies informed clinical care. The most common underlying disease states were NAFLD (n=85, 43%), viral hepatitis (n=50, 25%), and ALD (n=22, 11%). The primary endpoint was a composite of ascites, variceal bleeding, hepatic encephalopathy, hepatocellular carcinoma, liver transplantation and mortality. Binary cutoff values were predefined. Patients were followed for a median of 43 months. Over this period, 14 new clinical events were recorded, including 11 deaths. Technical failures were also reported (eg, poor quality scan); reliable measurements were obtained in 182 of 197 (92%) patients for multiparametric MRI and in 121 of 160 (76%) patients for transient elastography (transient elastography was additionally not attempted in 37 patients). The study was limited by having variable follow-up periods and the effect of patients being censored at different time points was not taken into account, so sensitivities, specificities, PPVs and NPVs should be interpreted cautiously. The CI for the survival analysis were wide likely due to the relatively small number of new clinical events observed.
 
Pavlides et al evaluated whether data obtained from multiparametric MRI was predictive of all-cause mortality and liver-related clinical events (Pavlides, 2016). Patients who were referred for a clinically indicated liver biopsy, or with a diagnosis of liver cirrhosis on MRI scan, were eligible. Liver-related clinical events were defined as liver-related death, hepatocellular carcinoma, and new hepatic decompensation (ie, clinically evident ascites, variceal bleeding, and hepatic encephalopathy). Patients received multiparametric MRI and liver cT1 values were mapped into a Liver Inflammation and Fibrosis (LIF) score. One hundred twenty three patients were recruited to the study; 6 were excluded due to claustrophobia or incomplete MRI data. Of the 117 patients who had complete MRI data, follow-up data were available for 112; the study reported outcomes on these 112 patients. The most common underlying disease states were NAFLD (35%), viral hepatitis (30%), and ALD (10%). Over a median follow-up time of 27 months, 10 patients had a liver-related clinical event and 6 patients died. No patients who had a LIF <2 (no or mild liver disease) developed a clinical event. Ten of 56 (18%) patients with a LIF 2 (moderate or severe liver disease) experienced a clinical event. A study limitation is the use of LIF scores, which are no longer used in clinical practice. The authors further described the study as a small proof of principle study.
 
Multiparametric MRI has been used as an alternative to biopsy for measuring fibrosis or cirrhosis in clinical trials. Phase 2 clinical trials have used multiparametric MRI to measure therapeutic efficacy of an investigational treatments for NASH and NAFLD (Harrison, 2018; Nakajima, 2021).
 
The utility of multiparametric MRI to provide clinically useful information on the presence and extent of liver fibrosis and inflammation has been evaluated in smaller prospective studies. Specifically, it has been evaluated in the setting of biochemical remission in liver diseases where noninvasive testing for continued disease activity could further aid in direct management of patients as a prognostic marker of future liver-related complications. Quantitative multiparametric MRI has been used to measure disease burden after treatment (ie, liver fibrosis and inflammation response to therapy) in patients with chronic HCV and pediatric autoimmune hepatitis (Jayaswal, 2021; Janowski, 2021; Arndtz, 2021; Bradley, 2019).
 
Liver histology is the gold standard to differentiate between steatohepatitis and simple steatosis and to assess fibrosis staging (Yumi, 2021). Currently, there are no acceptable noninvasive modalities to differentiate between bland steatosis and steatohepatitis.
 
Transient elastography and serum liver fibrosis markers (e.g., enhanced liver fibrosis test and FibroTest) may have a role in assessing fibrosis in compensated alcohol liver disease, and in following improvement of inflammation with recovery (Lucey, 2019; Crabb, 2020). At present, none of these have been adequately validated for routine clinical use in the diagnosis of alcoholic hepatitis.
 
Liver biopsy offers the only means of assessing both fibrosis and inflammation (Terrault, 2018). Elastography (preferred) and liver fibrosis biomarkers (e.g., FIB-4 or FibroTest) are alternative methods to assess fibrosis. If these noninvasive tests indicate significant fibrosis (F2), treatment is recommended.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A systematic review and meta-analysis conducted by Cianci et al evaluated the use of noninvasive biomarkers for prediction of all-cause and cardiovascular mortality in patients with NAFLD (Cianci, 2022). Of 24 studies included in the review, noninvasive scoring systems were assessed in 16 studies, 4 of which had adequate data for meta-analysis based on review criteria that required 2 or more studies reporting the same outcome measure using equivalent cut-off values and statistical methods in a similar study population. All of the studies included in the meta-analysis studies were retrospective (N=9,725; n range=320 to 4,680), and NAFLD diagnosis was based on liver biopsy or clinical diagnosis. Mean duration of follow-up ranged from 9 to 20 years in 3 of the studies and was not reported in the fourth study, but the total study duration was 17 years. A total of 1,697 deaths were reported in the 4 studies. Although high scores were associated with an increased risk of mortality relative to low scores across all scoring systems, the evidence is limited by the small number of included studies and high heterogeneity and imprecision for some estimates.
 
The utility of multiparametric MRI to provide clinically useful information on the presence and extent of liver fibrosis and inflammation has been evaluated in smaller prospective studies. Specifically, it has been evaluated in the setting of biochemical remission in liver diseases where noninvasive testing for continued disease activity could further aid in direct management of patients as a prognostic marker of future liver-related complications. Quantitative multiparametric MRI has been used to measure disease burden after treatment in patients with chronic HCV (Jayaswal, 2021) and autoimmune hepatitis (Janowski, 2021; Arndtz, 2021; Bradley, 2019; Bradley, 2019; Heneghan, 2022).
 
A 2022 consensus-based clinical care pathway was published by the AGA on risk stratification and management of NAFLD, including some recommendations regarding the use of non-invasive testing for individuals with chronic liver disease (Kanwal, 2021). Among individuals with increased risk of NAFLD or nonalcoholic steatohepatitis (NASH)-related fibrosis (i.e., individuals with type-2 diabetes, 2 metabolic risk factors, or an incidental finding of hepatic steatosis or elevated aminotransferases), assessment with a nonproprietary fibrosis scoring system such as FIB-4 is recommended, although aspartate transaminase to platelet ratio index can be used in lieu of FIB-4 scoring. Depending on the fibrosis score, imaging-based testing for liver stiffness may be warranted with transient elastography (FibroScan), although bidimensional shear wave elastography or point shear wave elastography are also imaging options included in the clinical care pathway.
 
A 2022 joint clinical practice guideline issued by the American Association of Clinical Endocrinology and American Association for the Study of Liver Diseases included the following recommendations on the use of noninvasive techniques for diagnosis of NAFLD with clinically significant fibrosis (stage F2 to F4) (Cusi, 2022):
 
  • Clinicians should use liver fibrosis prediction calculations to assess the risk of NAFLD with liver fibrosis. The preferred noninvasive initial test is the FIB-4 (Grade B, Level 2 evidence)
  • High-risk individuals with indeterminate or high FIB-4 score for further workup with an transient elastography or enhanced liver fibrosis test, as available (Grade B, Level 2 evidence)
  • Clinicians should prefer the use of transient elastography as best validated to identify advanced disease and predict liver-related outcomes. Alternative imaging approaches may be considered, including shear wave elastography (less well validated) and/or magnetic resonance elastography (most accurate but with a high cost and limited availability; best if ordered by liver specialist for selected cases) (Grade B, Level 2 evidence).
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Mozes et al found that all index tests evaluated (NFS, FIB-4, and FibroScan) performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD (Mozes, 2023).
 
A 2023 updated practice guidance issued by the AASLD included the following guidance statements on the use of noninvasive techniques for diagnosis and management of NAFLD and hepatic steatosis (Rinella, 2023).
 
    • All patients with hepatic steatosis or clinically suspected NAFLD based on the presence of obesity and metabolic risk factors should undergo primary risk assessment with FIB-4
    • In patients with pre-DM [diabetes mellitus], T2DM, or 2 or more metabolic risk factors (or imaging evidence of hepatic steatosis), primary risk assessment with FIB-4 should be repeated every 1–2 years
    • Although standard ultrasound can detect hepatic steatosis, it is not recommended as a tool to identify hepatic steatosis due to low sensitivity across the NAFLD spectrum
    • CAP [controlled attenuation parameter] as a point-of-care technique may be used to identify steatosis. MRI-PDFF [proton density fat fraction] can additionally quantify steatosis
    • If FIB-4 is 1.3, VCTE, MRE, or ELF [ Enhanced Liver Fibrosis] may be used to exclude advanced fibrosis
    • Improvement in ALT or reduction in liver fat content by imaging in response to an intervention can be used as a surrogate for histological improvement in disease activity

CPT/HCPCS:
76391Magnetic resonance (eg, vibration) elastography
76981Ultrasound, elastography; parenchyma (eg, organ)
76982Ultrasound, elastography; first target lesion
76983Ultrasound, elastography; each additional target lesion (List separately in addition to code for primary procedure)
91200Liver elastography, mechanically induced shear wave (eg, vibration), without imaging, with interpretation and report

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