Commercial

Medical Policy

Notification

Noninvasive Techniques for the Evaluation and Monitoring of Individuals with Chronic Liver Disease

Notification Issue Date:

This version of the policy went through a code update process effective 04/01/2020, and procedure codes 0014M and 0166U were added to this policy on that date.

Title:

Noninvasive Techniques for the Evaluation and Monitoring of Individuals with Chronic Liver Disease

Policy #:

06.02.56h

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

A single FibroSURE multianalyte assay, (i.e., either HCV FibroSURE, ASH FibroSURE, or NASH FibroSURE) is considered medically necessary and, therefore, covered for the evaluation of individuals with chronic liver disease.

Transient elastography (FibroScan) imaging is considered medically necessary for the evaluation of individuals with chronic liver disease.

NOT MEDICALLY NECESSARY

More than a single FibroSURE multianalyte assay, (i.e., either HCV FibroSURE, ASH FibroSURE, or NASH FibroSURE) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support its use for the evaluation of individuals with chronic liver disease, since each FibroSURE multianalyte assay is exclusive to a specific etiology for chronic liver disease (i.e., hepatitis C virus, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD).

EXPERIMENTAL/INVESTIGATIONAL

FibroSURE multianalyte assays are considered experimental/investigational and, therefore, not covered as repeat testing for monitoring of individuals with chronic liver disease because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Other multianalyte assays, (e.g., FIBROSpect or FIBROSpect II), with algorithmic analyses are considered experimental/investigational for the evaluation or monitoring of individuals with chronic liver disease because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Transient elastography (FibroScan) imaging is considered experimental/investigational and, therefore, not covered for monitoring of individuals with chronic liver disease because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

The use of other noninvasive imaging, including but not limited to multiparametric magnetic resonance imaging, acoustic radiation force impulse imaging (ARFI; e.g., Acuson S2000), or real-time tissue elastography, is considered experimental/investigational and, therefore, not covered for the evaluation or monitoring of individuals with chronic liver disease because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The Company may conduct reviews and audits of services to our members regardless of the participation status of the provider. Medical record documentation must be maintained on file to reflect the medical necessity of the care and services provided. These medical records may include but are not limited to: records from the professional provider’s office, hospital, nursing home, home health agencies, therapies, and test reports.

BILLING REQUIREMENTS

Inclusion of a code in this policy does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, a single FibroSURE multianalyte assay and transient elastography (FibroScan) imaging are covered, for the evaluation of individuals with chronic liver disease, under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

However, the following use for FibroSURE multianalyte assay and transient elastography (FibroScan) imaging has been identified in this policy as experimental/investigational and is, therefore, not eligible for coverage or reimbursement by the Company:

Monitoring of individuals with chronic liver disease

Subject to the terms and conditions of the applicable benefit contract, other multianalyte assays with algorithmic analyses (other than FibroSURE), and the use of other noninvasive imaging (other than FibroScan) are not eligible for payment under the medical benefits of the Company’s products because the service are considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

In November 2008, Acuson S2000™ Virtual Touch (Siemens AG, Erlanger, Germany), which provides acoustic radiation force impulse imaging, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process (K072786).

In August 2009, AIXPLORER® Ultrasound System (SuperSonic Imagine, Aix en Provence, France), which provides shear wave elastography, was cleared for marketing by FDA through the 510(k) process (K091970).

In June 2010, Hitachi HI VISION Preirus Diagnostic Ultrasound Scantier (Hitachi Medical Systems America, Twinsburg, OH), which provides real-time tissue elastography, was cleared for marketing by FDA through the 510(k) process (K093466).

In April 2013, FibroScan® (EchoSense SA, Paris, France), which uses transient elastography, was cleared for marketing by the U.S. Food and Drug Administration (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).

In August 2021, ADVIA Centaur ELF^TM test (Siemens Healthcare) was cleared for marketing by the FDA through the 513(f)(2) De Novo review pathway (DEN190056). In 2018, the device had been granted a Breakthrough Device designation.

FDA product codes: IYO, LNH, QQB.

Description

BIOPSY FOR CHRONIC LIVER DISEASE

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 individuals and then as a monitoring tool to assess response to therapy.

HEPATITIS C VIRUS

Infection with hepatitis C virus (HCV) can lead to permanent liver damage. Before noninvasive tests were available, liver biopsy is typically recommended before the initiation of antiviral therapy. Repeat biopsies may be performed to monitor fibrosis progression. Liver biopsies are analyzed according to a histologic scoring system; the most commonly used one for hepatitis C is the Metavir scoring system, which scores the presence and degree of inflammatory activity and fibrosis. The fibrosis is graded from F0 to F4, with a Metavir score of F0 signifying no fibrosis and F4 signifying cirrhosis (which is defined as the presence throughout the liver of fibrous septa that subdivide the liver parenchyma into nodules and represents the final and irreversible form of disease). The stage of fibrosis is the most important single predictor of morbidity and mortality in individuals with hepatitis C. Biopsies for hepatitis C are also evaluated according to the degree of inflammation present, referred to as the grade or activity level. For example, the Metavir system includes scores for necroinflammatory activity ranging from A0 to A3 (A0 = no activity, A1 = minimal activity, A2 = moderate activity, A3 = severe activity).

HEPATITIS B VIRUS

Most people who become infected with hepatitis B virus (HBV) recover fully, but a small portion will develop chronic HBV, which can lead to permanent liver damage. As with HCV, identification of liver fibrosis is needed to determine timing and management of treatment, and liver biopsy is the criterion standard for staging fibrosis. The grading of fibrosis in HBV also uses the Metavir system.

ALCOHOLIC LIVER DISEASE

Alcoholic liver disease (ALD) is the leading cause of liver disease in most Western countries. Histologic features of ALD usually include steatosis, alcoholic steatohepatitis (ASH), hepatocyte necrosis, Mallory bodies (tangled proteins seen in degenerating hepatocytes), a large polymorphonuclear inflammatory infiltrate, and, with continued alcohol abuse, fibrosis and possibly cirrhosis. The grading of fibrosis is similar to the scoring system used in hepatitis C. The commonly used Laënnec scoring system uses grades 0 to 4, with 4 being cirrhosis.

NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease (NAFLD) is defined as a condition that pathologically resembles ALD but occurs in individuals who are not heavy users of alcohol. It may be associated with a variety of conditions, including obesity, diabetes, and dyslipidemia. The characteristic feature of NAFLD is steatosis. At the benign end of the disease spectrum, there is usually no appreciable inflammation, hepatocyte death, or fibrosis. In contrast, nonalcoholic steatohepatitis (NASH), which shows overlapping histologic features with ALD, is an intermediate form of liver damage, and liver biopsy may show steatosis, Mallory bodies, focal inflammation, and degenerating hepatocytes. NASH can progress to fibrosis and cirrhosis. A variety of histologic scoring systems have been used to evaluate NAFLD. The NAFLD Activity Score (NAS) system for NASH includes scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2). Cases with scores of 5 or greater are considered NASH, while cases with scores of 3 and 4 are considered borderline (probable or possible) NASH. The grading of fibrosis is similar to the scoring system used in hepatitis C. The commonly used Laënnec scoring system uses grades 0 to 4, with 4 being cirrhosis.

NONINVASIVE ALTERNATIVES TO LIVER BIOPSY

MULTIANALYTE ASSAYS

A variety of noninvasive laboratory tests are being evaluated as alternatives to liver biopsy. Biochemical tests can be broadly categorized into indirect and direct markers of liver fibrosis. Indirect markers include liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), the ALT/AST ratio (also referred to as the AAR), platelet count, and prothrombin index. In recent years, there has been growing understanding of the underlying pathophysiology of fibrosis, leading to direct measurement of the factors involved. For example, the central event in the pathophysiology of fibrosis is activation of the hepatic stellate cell. Normally, stellate cells are quiescent but are activated in the setting of liver injury, producing a variety of extracellular matrix (ECM) proteins. In normal livers, the rate of ECM production equals its degradation, but, in the setting of fibrosis, production exceeds degradation. Metalloproteinases are involved in intracellular degradation of ECM, and a profibrogenic state exists when there is either a down regulation of metalloproteinases or an increase in tissue inhibitors of metalloproteinases (TIMP). Both metalloproteinases and TIMP can be measured in the serum, which directly reflects fibrotic activity. Other direct measures of ECM deposition include hyaluronic acid or α2- macroglobulin. While many studies have been done on these individual markers, or on groups of markers in different populations of individuals with liver disease, there has been interest in analyzing multiple markers using mathematical algorithms to generate a score that categorizes individuals according to the biopsy score. It is proposed that these algorithms can be used as an alternative to liver biopsy in individuals with liver disease. (Multianalyte assays with algorithmic analyses use the results from multiple assays of various types in an algorithmic analysis to determine and report a numeric score(s) or probability. The results of individual component assays are not reported separately). The following proprietary, algorithm-based tests are commercially available in the United States.

FIBROSURE and FIBROTEST

HCV FibroSURE

HCV FibroSURE (FibroTest) uses a combination of 6 serum biochemical indirect markers of liver function plus age and sex in a patented algorithm to generate a measure of fibrosis and necroinflammatory activity in the liver that correspond to the Metavir scoring system for stage (i.e., fibrosis) and grade (i.e., necroinflammatory activity). The measures are combined using a linear regression equation to produce a score between 0 and 1, with higher values corresponding to more severe disease. The biochemical markers include the readily available measurements of α2-macroglobulin, haptoglobin, bilirubin, γ-glutamyl transpeptidase (GGT), ALT, and apolipoprotein AI. Developed in France, the test has been clinically available in Europe under the name FibroTest since 2003 and is exclusively offered by LabCorp in the United States as HCV FibroSURE.

ASH FibroSURE

ASH FibroSURE (ASH Test) uses a combination of 10 serum biochemical markers of liver function together with age, sex, height, and weight in a proprietary algorithm and is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and ASH. The biochemical markers include α2-macroglobulin, haptoglobin, apolipoprotein AI, bilirubin, GGT, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name ASH Test and is exclusively offered by LabCorp in the United States as ASH FibroSURE.

NASH FibroSURE

NASH FibroSURE (NASH Test) uses a proprietary algorithm of the same 10 biochemical markers of liver function in combination with age, sex, height, and weight and is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and NASH. The biochemical markers include α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name NASH Test and is exclusively offered by LabCorp in the United States as NASH FibroSURE.

FIBROSpect II

FIBROSpect II uses a combination of 3 markers that directly measure fibrogenesis of the liver, analyzed with a patented algorithm. The markers include hyaluronic acid, TIMP-1, and α2-macroglobulin. FIBROSpect II is offered exclusively by Prometheus Laboratories. The measures are combined using a logistic regression algorithm to generate a FIBROSpect II index score, ranging from 1 to 100 (or sometimes reported between 0 and 1), with higher scores indicating more severe disease.

NONINVASIVE IMAGING TECHNOLOGIES
Noninvasive imaging technologies to detect liver fibrosis or cirrhosis among individuals with chronic liver disease are also being evaluated as alternatives to liver biopsy. The noninvasive imaging technologies include transient elastography (e.g., FibroScan), magnetic resonance elastography (MRE), acoustic radiation force impulse imaging (ARFI; e.g., Acuson S2000), and real-time tissue elastography (RTE; e.g., 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 low-frequency (50 Hz) waves, inducing an elastic shear wave that propagates throughout the liver. Ultrasound (US) tracks the wave, measuring its speed in kilopascals, 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 individuals 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)

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 (measured in meters per second) 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 individuals with a significant amount of ascites.

Real-Time Tissue Elastography (RTE)

RTE is a type of strain elastography that 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 individuals 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.

*Measurements obtained with LiverMultiscan protocol.

PEER-REVIEWED EVIDENCE REVIEW FOR VALIDATION OF CLINICAL USE OF NONINVASIVE ALTERNATIVES TO LIVER BIOPSY

LIVER BIOPSY AS A REFERENCE STANDARD

Liver biopsy is an imperfect reference standard. There is a high rate of sampling error in biopsy, which can lead to underdiagnosis of liver disease. This will bias estimates of performance characteristics of the noninvasive tests to which it is compared and must be considered in apprising the body of evidence. Mehta et al. estimated that, under the best scenario where sensitivity and specificity of liver biopsy are 90% and the prevalence of significant disease (Metavir ≥ F2) is 40%, even a perfect alternative marker would have calculated area under the receiver operating characteristic (AUROC) curve of 0.90. Therefore, effectiveness of alternative technologies may be underestimated. In fact, when the accuracy of biopsy is presumed to be 80%, a comparative technology with an AUROC curve of 0.76 may actually have an AUROC curve of 0.93 to 0.99 for diagnosing true disease. Although options exist for performing systematic reviews with imperfect reference standards, the majority of available reviews on this topic did not use any correction for the imperfect reference.

SYSTEMATIC REVIEWS INCLUDING MULTIPLE NONINVASIVE TESTS

Due to the large number of primary studies published on this topic, this evidence review focuses on systematic reviews when available. The validation of multiple noninvasive tests will be assessed individually in the following sections. In this section, systematic reviews that compare several noninvasive tests will be discussed.

In a 2013 systematic review, Chou and Wasson evaluated the accuracy of a wide variety of blood tests in determining fibrosis and/or cirrhosis. Both “simple” tests (e.g., platelet count) and more complex scoring systems (e.g., the FibroTest and FibroIndex) were included. A total of 172 studies were identified that compared the diagnostic accuracy of blood tests with liver biopsy. Blood tests associated with AUROC curves of 0.70 or greater (range, 0.70-0.86) were considered fair to good for identifying fibrosis, and AUROC curves of 0.80 or greater (range, 0.80-0.91) were considered good to excellent for identifying cirrhosis. Tests for identifying clinically significant fibrosis with AUROC curves of 0.70 to 0.86 included platelet count, age-platelet index, aspartate aminotransferaseplatelet ratio index (APRI), FibroIndex, FibroTest, and Forns index with median positive likelihood ratios of 5 to 10 at commonly used cutoffs. Tests for identifying cirrhosis with AUROC curves of 0.80 to 0.91 included platelet count, age-platelet index, APRI, and HepaScore also with median positive likelihood ratios of 5 to 10. Most tests did not have high negative predictive values (NPV) for fibrosis, and negative likelihood ratios were found in the moderately useful range (0.10-0.20) at commonly used cutoffs, only with FibroIndex and FibroTest. This suboptimal NPV suggests that these tests perform better in identifying fibrosis than in ruling it out. Additionally, differences were small between the FibroTest or APRI and other blood tests, suggesting routinely available blood tests and simple calculations are not outperformed by additional blood tests and more complex algorithms in identifying fibrosis.

The systematic review by Crossan et al. (2015) was performed for the Health Technology Assessment (HTA) program of the National Institute for Health Research. 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 individuals 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. individuals with HCV were the most common population included in the studies while individuals 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.

In 2016, Houot et al. reported on a systematic review funded by BioPredictive, the manufacturer of FibroTest. 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.

SYNOPSES FOR THE STATE OF EVIDENCE FOR VALIDATION OF CLINICAL USE OF NONINVASIVE ALTERNATIVES TO LIVER BIOPSY

MULTIANALYTE ASSAYS

FibroSURE and FibroTest

FibroSURE (FibroTest) is the most widely validated of the noninvasive commercial serum tests. It has been studied in populations with viral hepatitis, NAFLD, and ALD. Although there are established cutoffs for positivity for FibroTest, they were not consistently used in validation studies. The methodologic quality of the validation studies was generally poor. There is no direct evidence that FibroSURE (FibroTest) improves health outcomes. However, FibroTest has been allowed as an alternative to biopsy to establish trial eligibility in terms of fibrosis or cirrhosis in several randomized controlled trials (RCTs) that established the efficacy of HCV treatments.

FIBROSpect II

FIBROSpect II has been studied in populations with HCV. Cutoffs for positivity varied across studies and were not well validated. The methodologic quality of the validation studies was generally poor. There is no direct evidence that FIBROSpect II improves health outcomes.

Other Multianalyte Scoring Systems

Other scoring systems have been developed. For example, the APRI requires only the serum level of AST and the number of platelets, and uses a simple nonproprietary formula that can be calculated at the bedside to produce a score for the prediction of fibrosis.39 Using an optimized cutoff value derived from a training set and validation set of patients with HCV, authors have reported that the NPV for fibrosis was 86% and that the PPV was 88%. In Crossan et al. (2015), APRI was frequently evaluated and has been tested in HCV, HBV, NAFLD, and ALD.

Rosenberg et al developed a scoring system based on an algorithm combining hyaluronic acid, amino terminal propeptide of type III collagen, and TIMP-1. The algorithm was developed in a test set of 400 patients with a wide variety of chronic liver diseases and then validated in another 521 patients. The algorithm was designed to discriminate between no or mild fibrosis and moderate-to-severe fibrosis. The NPV for fibrosis was 92%.

Giannini et al. reported that use of the AST/ALT ratio and platelet counts in a diagnostic algorithm would have avoided liver biopsy in 69% of their patients and would have correctly identified the absence/presence of significant fibrosis in 80.5% of these cases. In Crossan et al (2015), the cutoffs for positivity of AST/ALT ratio for diagnosis of significant fibrosis (stage ≥ F2) varied from 0.6 to 1 in 7 studies.6 Summary sensitivity and specificity were 44% (95% CI, 27% to 63%) and 71% (95% CI, 62% to 78%), respectively. Thirteen studies used a cutoff of 1 to estimate diagnostic accuracy of cirrhosis with AST/ALT ratio, and summary sensitivity and specificity were 49% (95% CI, 39% to 59%) and 87% (95% CI, 75% to 94%), respectively.

A number of studies have compared HCV FibroSURE (FibroTest) and other noninvasive tests of fibrosis with biopsy using ROC analysis. For example, Bourliere et al reported validation of FibroSURE (FibroTest) and found that, based on ROC analysis, FibroSURE (FibroTest) was superior to APRI for identifying significant fibrosis, with AUROC curves of 0.81 and 0.71, respectively. A 2012 prospective multicenter study from France compared 9 of the best-evaluated blood tests in 436 patients with hepatitis C and found similar performance for HCV FibroSURE (FibroTest), FibroMeter, and HepaScore (ROC curve, 0.84, 0.86, 0.84, respectively). These 3 tests were significantly superior to the 6 other tests, with 70% to 73% of patients considered well classified according to a dichotomized score (F0/F1 vs ≥F2). The number of “theoretically avoided liver biopsies” for the diagnosis of significant fibrosis was calculated to be 35.6% for HCV FibroSURE (FibroTest). To improve diagnostic accuracy, algorithms that combine HCV FibroSURE (FibroTest) with other tests (eg, APRI) are also being evaluated. One of these, the sequential algorithm for fibrosis evaluation (SAFE), combines the APRI and FibroTest. Crossan et al. (2015) reported that the algorithm has been assessed in 4 studies of HCV for diagnosing both significant fibrosis (stage ≥ F2) and cirrhosis.6 Summary sensitivity and specificity for significant fibrosis were estimated to be 100% (95% CI, 100% to 100%) and 81% (95% CI, 80% to 83%) , respectively. The summary sensitivity and specificity for cirrhosis were 74% (95% CI, 42% to 92%) and 93% (95% CI, 91% to 94%), respectively.

NONINVASIVE IMAGING

The following noninvasive imaging types are reviewed here: transient elastography (e.g., FibroScan), magnetic resonance elastography (MRE), acoustic radiation force impulse imaging (ARFI; e.g., Acuson S2000), and real-time tissue elastography (RTE; e.g., HI VISION Preirus).

Transient Elastography (FibroScan)

Transient elastography (FibroScan) is the most widely validated of the noninvasive methods. FibroScan has been studied in populations with viral hepatitis, NAFLD, and ALD. FibroScan validation studies have suggested that it can provide good detection of significant fibrosis and good-to-excellent detection of cirrhosis compared to liver biopsy for HCV and HBV. There are limited data on NAFLD and ALD. There are no established or validated cutoffs, and the quality of the validation studies was generally not high. Failures of the test are not uncommon, particularly for those with high BMI, but were frequently not captured in analyses of the validation studies. Newer more sensitive probes may lessen this limitation. There is no direct evidence that FibroScan improves health outcomes. However, FibroScan has been allowed as an alternative to biopsy to diagnose fibrosis or cirrhosis to establish trial eligibility in several RCTs that established efficacy of HCV treatments.

Acoustic Radiation Force Impulse Imaging (ARFI)

ARFI has been evaluated in viral hepatitis and NAFLD. ARFI has potential advantages over FibroScan; it can be implemented on a standard ultrasound machine, may be more applicable for assessing complications such as ascites and may be more applicable in obese patients. ARFI appears to have similar diagnostic accuracy to FibroScan, but there are fewer data available on performance characteristics. Validation studies have used varying cutoffs for positivity.

Real-Time Tissue Elastography (HI VISION 15 Preirus)

RTE has been evaluated in multiple diseases with varying scoring methods and cutoffs. Although data are limited, the accuracy of RTE appears to be similar to FibroScan for the evaluation of significant liver fibrosis, but less accurate for the evaluation of cirrhosis. However, there was evidence of publication bias in the systematic review and the diagnostic accuracy may be overestimated.

Combined Use of Multianalyte Assays and Noninvasive Imaging

The combined use of multianalyte assays with algorithmic analyses and noninvasive imaging has been considered for evaluating fibrosis in patients with chronic liver disease. Few studies have evaluated the incremental accuracy of the combined use of tests. One such algorithm was described by Castera et al (2010) and is called the Bordeaux algorithm. It is a synchronous test of FibroTest and FibroScan that was developed in patients with HCV. The algorithm states that if FibroScan 0.48, then fibrosis stage is ≥F2. If there is disagreement between the 2 tests then a biopsy is performed. Crossan et al. (2015) found 1 study describing the performance characteristics of the Bordeaux algorithm in HCV for detecting significant (stage ≥F2) fibrosis. Summary sensitivity and specificity were 88% (95% CI, 85% to 91%) and 89% (95% CI, 85% to 92%), respectively. For detecting cirrhosis, summary sensitivity and specificity from 1 study were 87% (95% CI, 80% to 92%) and 95% (95% CI, 93% to 96%), respectively.

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.

Multiparametric Magnetic Resonance Imaging

There are currently no published studies of direct evidence to demonstrate the effect on patient outcomes. 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.

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 (i.e., liver fibrosis and inflammation response to therapy)in patients with chronic HCV, and pediatric autoimmune hepatitis.

Currently, there is not evidence that demonstrates that the use of the test for response to therapy impacts decision making and that these changes in management decisions lead to improved outcomes.

PRACTICE GUIDELINES AND POSITION STATEMENTS

NONALCOHOLIC FATTY LIVER DISEASE
American Gastroenterological Association et al.

The 2012 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 (AASLD), and the American College of Gastroenterology (ACG) do not reference multianalyte assays with algorithmic analyses (MAAAs) for liver fibrosis evaluation and management.

National Institute for Health and Care Excellence

In July 2016, the National Institute for Health and Care Excellence (NICE) published guidance on the assessment and management of NAFLD. The guidance did not reference elastography or MAAAs. The guidance recommended the enhanced liver fibrosis test to test for advanced liver fibrosis.

ALCOHOLIC LIVER DISEASE
American College of Gastroenterology (ACG)

The 2010 ACG guidelines on alcoholic liver disease do not reference elastography or MAAAs.

HEPATITIS B and C VIRUSES
National Institute for Health and Care Excellence

In June 2013, NICE published guidance on the management and treatment of individuals with hepatitis B. The guidance recommended offering transient elastography as the initial test in adults diagnosed with chronic hepatitis B, to inform the antiviral treatment decision. As of September 2016, NICE has placed a pause on the development of the guidance on hepatitis C, citing instability and costs in the availability of treatments for the condition.

American Association for the Study of Liver Diseases and Infectious Diseases Society of America

The 2016 AASLD and Infectious Diseases Society of America (IDSA) guidelines for testing, managing, and treating hepatitis C virus (HCV) recommend that for counseling and pretreatment assessment purposes, the following should be completed:

“Evaluation for advanced fibrosis, using liver biopsy, imaging, 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]”

The guidelines note that there are several noninvasive tests to stage the degree of fibrosis in individuals with hepatitis C. Tests included indirect serum biomarkers, direct serum biomarkers, and vibration-controlled liver elastography. The guidelines assert that no single method is recognized to have high accuracy alone and careful interpretation of these tests is required.

CHRONIC LIVER DISEASE

European Association for the Study of Liver Disease et al.

The European Association for the Study of Liver Disease and the Asociacion Latinoamericana para el Estudio del Higado (EASL-ALEH) convened a panel of experts to develop clinical practice guidelines on the use of noninvasive tests to evaluate liver disease severity and prognosis, with results published in 2015. The publication provided a summary of the advantages and disadvantages of noninvasive techniques (serum biomarkers, imaging techniques).

SUMMARY

Noninvasive techniques to monitor liver fibrosis are being investigated as alternatives to liver biopsy in individuals with chronic liver disease. Options for noninvasive monitoring include (1) multianalyte serum assays with algorithmic analysis of either direct or indirect biomarkers and (2) specialized radiologic methods, including multiparametric MRI, transient elastography, acoustic radiation force impulse imaging (ARFI), and real-time transient elastography (RTE).

For individuals who have chronic liver disease who receive transient elastography, the evidence includes many systematic reviews of more than 50 observational studies (>10,000 individuals). Relevant outcomes are test accuracy and validity, morbid events, and treatment-related morbidity. Transient elastography (FibroScan) has been studied in populations with viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). There are varying cutoffs for positivity. Failures of the test are not uncommon, particularly for those with high body mass index, but were frequently not captured in analyses of the validation studies. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. However, for the purposes of deciding whether a individual has severe fibrosis or cirrhosis, the FibroScan results provide data sufficiently useful to determine therapy.

Specifically, FibroScan has been used as an alternative to biopsy to establish eligibility regarding presence of fibrosis or cirrhosis in several randomized controlled trials (RCTs) that showed the efficacy of hepatitis C virus (HCV) treatments, which in turn demonstrated that the test can identify individuals who would benefit from therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic liver disease who noninvasive radiologic methods other than transient elastography for liver fibrosis measurement, the evidence includes systematic reviews of observational studies. Relevant outcomes are test accuracy and validity, morbid events, and treatment-related morbidity. Other radiologic methods (AFRI, RTE) may have similar performance for detection of significant fibrosis or cirrhosis. Studies have frequently included varying cutoffs not prespecified or validated. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. There is no direct evidence that other noninvasive radiologic methods improve health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic liver disease who receive FibroSURE (FibroTest) serum panels, the evidence includes systematic reviews of more than 30 observational studies (>5000 individuals). Relevant outcomes are test accuracy and validity, morbid events, and treatment-related morbidity. FibroSURE has been studied in populations with viral hepatitis, NAFLD, and ALD. There are established cutoffs, although they were not consistently used in validation studies. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. However, for the purposes of deciding whether a individual has severe fibrosis or cirrhosis, FibroSURE result provide data sufficiently useful to determine therapy. Specifically, FibroSURE has been used as an alternative to biopsy to establish eligibility regarding the presence of fibrosis or cirrhosis in several RCTs that showed the efficacy of HCV treatments, which in turn demonstrated that the test can identify individuals who would benefit from therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic liver disease who receive multianalyte serum assays other than FibroSURE (FibroTest), the evidence includes systematic reviews of observational studies. Relevant outcomes are test accuracy and validity, morbid events, and treatment-related morbidity. Studies have frequently included varying cutoffs, some of which were standardized and others not validated. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. There is no direct evidence that other multianalyte serum assays improve health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic liver disease who receive multiparametric MRI, the evidence includes several prospective and retrospective observational studies. Multiparametric MRI (e.g., LiverMultiScan) has been studied in mixed populations, including NAFLD, viral hepatitis, and ALD. Quantitative MRI provides various measures assessing both liver fat content and fibrosis and inflammation. Various cutoffs have been utilized for positivity. Generally, multiparametric MRI performed similarly to transient elastography, and fewer technical failures of multiparametric MRI were reported. Given these limitations and the imperfect reference standard, it can be difficult to interpret performance characteristics. The prognostic ability of quantitative MRI to predict liver-related clinical events has been evaluated in 2 studies; both reported positive correlations, but the Confidence Intervals were wide. Larger cohorts with a longer follow-up time would be useful to further derive the prognostic ability. Additionally, multiparametric MRI has been used to measure the presence of fibrosis or cirrhosis in the patients who have achieved biochemical remission after treatment only in small prospective studies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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Coding

CPT Procedure Code Number(s)

MEDICALLY NECESSARY

0001M, 0002M, 0003M, 76981, 76982, 76983, 81596, 91200

EXPERIMENTAL/INVESTIGATIONAL

0166U, 0344U, 0648T, 0649T, 81517

THE FOLLOWING CODE IS USED TO REPRESENT ALL COMPONENTS OF FIBROSPECT

84999

THE FOLLOWING CODES MAY BE USED TO REPRESENT THE INDIVIDUAL COMPONENTS OF FIBROSPECT

For hyaluronic acid, and tissue inhibitor of metalloproteinase (TIMP-1):

83520

For α2-macroglobulin:

83883

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

K70.0 Alcoholic fatty liver

K70.10 Alcoholic hepatitis without ascites

K70.11 Alcoholic hepatitis with ascites

K70.2 Alcoholic fibrosis and sclerosis of liver

K70.30 Alcoholic cirrhosis of liver without ascites

K70.31 Alcoholic cirrhosis of liver with ascites

K70.40 Alcoholic hepatic failure without coma

K70.9 Alcoholic liver disease, unspecified

K71.0 Toxic liver disease with cholestasis

K71.10 Toxic liver disease with hepatic necrosis, without coma

K71.3 Toxic liver disease with chronic persistent hepatitis

K71.4 Toxic liver disease with chronic lobular hepatitis

K71.50 Toxic liver disease with chronic active hepatitis without ascites

K71.51 Toxic liver disease with chronic active hepatitis with ascites

K71.6 Toxic liver disease with hepatitis, not elsewhere classified

K71.7 Toxic liver disease with fibrosis and cirrhosis of liver

K71.8 Toxic liver disease with other disorders of liver

K71.9 Toxic liver disease, unspecified

K72.10 Chronic hepatic failure without coma

K73.0 Chronic persistent hepatitis, not elsewhere classified

K73.1 Chronic lobular hepatitis, not elsewhere classified

K73.2 Chronic active hepatitis, not elsewhere classified

K75.3 Granulomatous hepatitis, not elsewhere classified

K73.8 Other chronic hepatitis, not elsewhere classified

K73.9 Chronic hepatitis, unspecified

K74.00 Hepatic fibrosis, unspecified

K74.01 Hepatic fibrosis, early fibrosis

K74.02 Hepatic fibrosis, advanced fibrosis

K74.1 Hepatic sclerosis

K74.2 Hepatic fibrosis with hepatic sclerosis

K74.3 Primary biliary cirrhosis

K74.4 Secondary biliary cirrhosis

K74.5 Biliary cirrhosis, unspecified

K74.60 Unspecified cirrhosis of liver

K74.69 Other cirrhosis of liver

K75.4 Autoimmune hepatitis

K75.81 Nonalcoholic steatohepatitis (NASH)

K76.0 Fatty (change of) liver, not elsewhere classified

K76.1 Chronic passive congestion of liver

HCPCS Level II Code Number(s)

N/A

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 06.02.56h:

01/02/2024

Inclusion of a policy in a Code Update memo does not imply that a full review of the policy was completed at this time.

This version of the policy has been identified for a CPT code update, effective 01/02/2024.

The following procedure code was removed from the policy : 0014M

The following procedure code was added to this policy : 81517

Revisions From 06.02.56g:

05/31/2023	This policy has been reissued in accordance with the Company's annual review process.
10/01/2022	This policy went through a code update effective 10/01/2022. The following procedure code was added to the policy with a position of E/I: 0344U

Revisions From 06.02.56f:

03/28/2022

This policy has been updated to provide rationale for

multiparametric magnetic resonance imaging being considered experimental/investigational and, therefore, not covered for the evaluation or monitoring of individuals with chronic liver disease because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

All information related to magnetic resonance

elastography (MRE) has been removed from this policy bulletin. MRE for liver is managed by AIM for the Company.

Revisions From 06.02.56e:

01/01/2022

This policy has been identified and updated for the CPT/HCPCS code update effective 01/01/2022.

The following CPT codes have had narrative revisions:
0648T and 0649T

Revisions From 06.02.56d:

07/01/2021

This version of the policy went through a code update process effective 07/01/2021, and procedure codes 0648T and 0649T were added to this policy on that date.

Revisions From 06.02.56c:

10/07/2020	This policy has been reissued in accordance with the Company's annual review process.
10/01/2020	This version of the policy went through a code update process effective 10/01/2020. Diagnosis code K74.0 was deleted. Diagnosis codes K74.00, K74.01, and K74.02.

Revisions From 06.02.56b:

04/01/2020

This version of the policy went through a code update process effective 04/01/2020, and procedure codes 0014M and 0166U were added to this policy on that date.

Revisions From 06.02.56a:

05/08/2019	This policy has been reissued in accordance with the Company's annual review process.
01/01/2019	Effective 01/01/2019, the following procedure codes have been added to this policy due to coding updates: 81596 76981 76982 76983

Revisions From 06.02.56:

09/12/2018

The policy has been reviewed and reissued to communicate the Company’s continuing position on Noninvasive Techniques for the Evaluation and Monitoring of Individuals with Chronic Liver Disease.

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

1/2/2024

Version Issued Date:

1/2/2024

Version Reissued Date: