Noninvasive Techniques for the Evaluation and Monitoring of Patients With Chronic Liver Disease

POLICY NUMBER

A.2.04.41

DESCRIPTION

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

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 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 (no or minimal inflammation) to 4 (severe) and fibrosis from 0 (no fibrosis) to 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 to monitor response to therapy.

Hepatitis C Virus

Infection with hepatitis C virus (HCV) can lead to permanent liver damage. Prior to noninvasive testing, liver biopsy was 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 HCV is the Metavir 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, representing the final and irreversible form of the disease). The stage of fibrosis is the most important single predictor of morbidity and mortality in patients with hepatitis C. Biopsies for HCV 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 HCV. 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 patients who are not heavy users of alcohol. Moreover, NAFLD 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, non-alcoholic 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 system for NASH includes scores for steatosis (0 to 3), lobular inflammation (0 to 3), and ballooning (0 to 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 Laennec scoring system uses grades 0 to 4, with 4 being cirrhosis.

Of note, in 2023, NAFLD was renamed to metabolic dysfunction-associated steatotic liver disease (MASLD) due to concerns over exclusionary and stigmatizing language. A consensus-driven process found that the new term better reflects the metabolic nature of the disease. Similarly, NASH was renamed to metabolic-dysfunction associated steatohepatitis (MASH). Additionally, a new term, metabolic and alcohol-related/associated liver disease (MetALD) was introduced to characterize disease with both metabolic dysfunction and significant alcohol intake. Due to this recent change, unless a publication specifically refers to MASLD or MASH, the abbreviations NAFLD and NASH, respectively, will continue to be used throughout this policy.

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. There has been a growing understanding of the underlying pathophysiology of fibrosis, leading to a direct measurement of the factors involved. For example, the central event in the pathophysiology of fibrosis is the 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 with 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. Both metalloproteinases and tissue inhibitors of metalloproteinases can be measured in the serum, which directly reflects the fibrotic activity. Other direct measures of ECM deposition include hyaluronic acid or alpha-2 macroglobulin.

While many studies have been done on these individual markers, or on groups of markers in different populations of patients with liver disease, there has been interest in analyzing multiple markers using mathematical algorithms to generate a score that categorizes patients according to the biopsy score. It is proposed that these algorithms can be used as alternatives to liver biopsy in patients with liver disease. The following proprietary, algorithm-based tests are commercially available in the United States.

There are 3 different FibroSURE tests available depending on the indication for use: HCV FibroSURE, ASH FibroSURE, and NASH FibroSURE.

HCV FibroSURE

The HCV FibroSURE 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 corresponds 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 alpha-2 macroglobulin, haptoglobin, bilirubin, y-glutamyl transpeptidase, 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 U.S. 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; the test is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and ASH. The biochemical markers include alpha-2 macroglobulin, haptoglobin, apolipoprotein AI, bilirubin, γ-glutamyl transpeptidase, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name ASHTest™ (BioPredictive); the test 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 alpha-2 macroglobulin, haptoglobin, apolipoprotein AI, bilirubin, γ-glutamyl transpeptidase, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name NASHTest™ (BioPredictive); the test 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, tissue inhibitor of metalloproteinase 1, and alpha-2 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.

Enhanced Liver Fibrosis Test

The Enhanced Liver Fibrosis (ELF) test uses a proprietary algorithm to produce a score based on 3 serum biomarkers involved in matrix biology: hyaluronic acid, Procollagen III amino terminal peptide and tissue inhibitor of metalloproteinase 1. The manufacturer recommends the following cutoffs for interpretation for risk of development of cirrhosis or liver-related events in patients with NASH: <9.80 (lower risk) and ≥11.30 (higher risk).

Noninvasive Imaging Technologies

Noninvasive imaging technologies to detect liver fibrosis or cirrhosis among patients with chronic liver disease are being evaluated as alternatives to liver biopsy. The noninvasive imaging technologies include transient elastography (eg, FibroScan), magnetic resonance elastography, acoustic radiation force impulse imaging (ARFI; eg, Acuson S2000), multiparametric magnetic resonance imaging (MRI), and real-time tissue elastography (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 low-frequency (50 Hz) waves, inducing an elastic shear wave that propagates throughout the liver. Ultrasound 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 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 imaging uses an ultrasound 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 patients with a significant amount of ascites.

Magnetic Resonance Elastography

Magnetic resonance elastography uses a driver to generate 60-Hz mechanical waves on the patient’s chest wall. The magnetic resonance 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. Magnetic resonance elastography has several advantages over ultrasound elastography, including: (1) the ability to analyze larger liver volumes; (2) the ability to analyze liver volumes of obese patients or patients with ascites; and (3) the ability to precisely analyze viscoelasticity using a 3-dimensional displacement vector.

Real-Time Tissue Elastography

Real-time tissue elastography 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 ultrasound images in real time. Hitachi manufactures real-time tissue elastography devices, including the 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. Real-time tissue elastography 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.

In 2008, Acuson S2000™ Virtual Touch (Siemens AG), 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 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 real-time tissue elastography, was cleared for marketing by the 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).

In August 2021, ADVIA Centaur Enhanced Liver Fibrosis (ELF™) 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 for predicting disease progression in patients with advanced fibrosis due to NAFLD.

In July 2023, the Enhanced Liver Fibrosis (ELF™) Test was granted a Breakthrough Device Designation to aid in the identification of advanced fibrosis (≥F3) and cirrhosis (F4) in patients with NAFLD.

POLICY

A single FibroSURE multianalyte assay may be considered medically necessary for the evaluation of individuals with chronic liver disease.

FibroSURE multianalyte assays are considered investigational for monitoring of individuals with chronic liver disease.

Other multianalyte assays with algorithmic analyses are considered investigational for the evaluation or monitoring of individuals with chronic liver disease.

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

Transient elastography (FibroScan) imaging is considered investigational for monitoring of individuals with chronic liver disease.

The use of other non-invasive imaging, including but not limited to magnetic resonance elastography, multiparametric magnetic resonance imaging, acoustic radiation force impulse imaging (eg, Acuson S2000), or real-time tissue elastography, is considered investigational for the evaluation or monitoring of individuals with chronic liver disease.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

09/27/2012: New policy added.

09/16/2014: Policy reviewed; description updated. Policy statement unchanged. Sources section updated to change "2.01.84" to "2.04.41."

04/01/2015: Policy title changed from "Multianalyte Assays with Algorithmic Analysis for the Evaluation and Monitoring of Patients with Chronic Liver Disease" to "Non-invasive Techniques for the Evaluation and Monitoring of Patients With Chronic Liver Disease." Policy description updated regarding non-invasive alternatives to liver biopsy. First investigational policy statement updated to change "diagnosis" to "evaluation." Added the following investigational policy statement: The use of non-invasive 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. Added CPT codes 0001M, 0002M, 0003M, 91299, and 91200 to the Code Reference section. Removed ICD-9 diagnosis code range 570-573.9.

07/31/2015: Code Reference section updated for ICD-10.

06/06/2016: Policy number A.2.04.41 added. Investigative definition updated in Policy Guidelines section.

04/16/2018: Policy description updated regarding Hepatitis B Virus, HCV FibroSURE, and FIBROSpect II. Added the following policy statements: 1) A single FibroSURE multianalyte assay may be considered medically necessary for the evaluation of patients with chronic liver disease. 2) FibroSURE multianalyte assays are considered investigational for monitoring patients with chronic liver disease. 3) Transient elastography (FibroScan) imaging may be considered medically necessary for the evaluation of patients with chronic liver disease. 4) Transient elastography (FibroScan) imaging is considered investigational for monitoring patients with chronic liver disease. Policy Guidelines updated regarding multianalyte assays. Code Reference section updated to change non-covered codes table to medically necessary codes table. Added CPT code 0346T and removed CPT codes 84999 and 91299. Added ICD-10 diagnosis codes B18.0 - B18.9, K70.0 - K70.9, K71.0 - K71.9, K72.00 - K72.91, K73.0 - K73.9, K74.0 - K74.69, K75.0 - K75.9, K76.0 - K76.9, and K77.

10/01/2018: Code Reference section updated to revise description for CPT code 0001M.

12/18/2018: Code Reference updated to add new CPT codes 76981, 76982, 76983, and 81596 to the medically necessary codes table. Added new CPT code 76391 as investigational, effective 01/01/2019.

01/21/2019: Policy description updated. Policy statements unchanged.

12/10/2019: Policy description updated regarding devices. Policy statements unchanged.

09/28/2020: Code Reference section updated to add new ICD-10 diagnosis codes K74.00, K74.01, and K74.02, effective 10/01/2020. Removed deleted CPT code 0346T.

01/14/2021: Policy description updated regarding devices. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders."

06/18/2021: Code Reference section updated to add new CPT codes 0648T and 0649T, effective 07/01/2021.

12/13/2021: Code Reference section updated to revise code description for CPT codes 0648T and 0649T, effective 01/01/2022. Removed deleted ICD-10 diagnosis code, K74.0.

09/13/2022: Code Reference section updated to add new CPT code 0344U. Effective 10/01/2022.

10/25/2022: Policy description updated regarding the enhanced liver fibrosis test, multiparametric magnetic resonance imaging, and devices. Policy section updated to include multiparametric magnetic resonance imaging as investigational for the evaluation or monitoring of patients with chronic liver disease. Code Reference section updated to remove deleted CPT code 0001M and add CPT codes 0014M and 0166U.

01/20/2023: Policy reviewed. Policy statements updated to change "patients" to "individuals."

12/21/2023: Policy reviewed. Policy statements unchanged. Code Reference section updated to add new 2024 CPT code 81517, effective 01/01/2024.

07/01/2024: Code Reference section updated to add new CPT code 0468U as investigational.

02/05/2025: Policy description updated regarding nonalcoholic fatty liver disease and devices. Policy statements unchanged. Code Reference section updated to remove deleted CPT code 0014M.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.41 

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.