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.

Disease Background

Chronic liver disease (CLD) is associated with approximately two million annual deaths worldwide. CLD is a progressive deterioration of liver function for more than 6 months, adversely affecting synthesis of clotting factors, other proteins, detoxification of harmful products of metabolism, and excretion of bile. CLD is a continuous process of inflammation, destruction, and regeneration of liver parenchyma, which leads to fibrosis and cirrhosis. Multiple etiologies are associated with CLD including toxin exposures, chronic alcohol abuse, infection, autoimmune diseases, genetic and metabolic disorders. CLD is the 9th cause of death in the United States (U.S.). According to the National Center for Health Statistics from the U.S. Center for Disease Control and Prevention, approximately 4.5 million adults had CLD and cirrhosis. This represents 1.8 percent of the adult population. There were 52,222 deaths through 2023 (15.6 deaths per 100,000 population) from CLD and cirrhosis.

Steatosis (also known as fatty liver disease) is a condition caused by an excessive buildup of fat in the liver. Steatotic liver disease (SLD) is a generic term for the accumulation of lipids in liver parenchymal cells. Primary risk factors for SLD include alcohol, insulin resistance, and obesity. In 2023, a global consensus conference described 5 subclasses of SLD: metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD); alcohol-associated liver disease (ALD); SLD with specific etiology (e.g., drug-induced); cryptogenic SLD, and MASLD with increased alcohol intake (MetALD).

The Brunt-Kleiner scoring system and the NASH Clinical Research Network (CRN) scoring system (i.e., NAFLD Activity Score, NAS) are two of the most widely used methods for histologically assessing steatosis and fibrosis in MASLD. The Brunt-Kleiner system has four possible grades (0-3) and five possible stages (0-4). The NAS is an 8-point scale classifying the severity of steatosis (score: 0-3), lobular inflammation (score: 0-3) and ballooning (score: 0-2), with greater scores equating more severe disease. Both systems determine the degree of steatosis based on the percentage of steatotic hepatocytes involved: normal <5%, mild =5% to 33%, moderate =34% to 66%, and severe >66%.

Fibrosis scores are generally disease-specific and technically cannot be unified across different CLDs. To achieve a unified approach, the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines Committee incorporated the different fibrosis staging systems by consolidating them into a single framework. The AASLD defined three primary categories: "at least significant fibrosis," corresponding to fibrosis stage 2 or higher (F2-4); "at least advanced fibrosis," encompassing stages F3 and F4; and "cirrhosis," represented by stage F4 (Table 1).

Table 1. Staging of Fibrosis across Multiple Etiologies*

* Adapted from American Association for the Study of Liver Diseases (AASLD) Practice Guidelines (2025)

ALD: Alcohol-associated liver disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; PBC: Primary biliary cirrhosis; PSC: Primary Sclerosing Cholangitis

Non-Infectious Etiologies

Alcohol-Associated Liver Disease

ALD is a major cause of liver disease worldwide, both on its own and as a co-factor in the progression of chronic viral hepatitis, MASLD, iron overload, and other liver diseases. ALD represents a spectrum of liver injury resulting from alcohol use, ranging from steatosis to steatohepatitis and cirrhosis. ALD progression relies on persistent alcohol use and factors such as genetics, sex, diet, and concurrent liver conditions.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) formerly Nonalcoholic Fatty Liver Disease (NAFLD)

In 2023, the AASLD and other professional societies adopted new nomenclature for the spectrum of NAFLD. The new terminology reflected the role of metabolic dysfunction in the development of what is now termed MASLD. Given this recent nomenclature shift, this policy will continue to use the abbreviations NAFLD and NASH (nonalcoholic steatohepatitis) unless a publication specifically refers to MASLD or MASH (metabolic dysfunction-associated steatohepatitis).

MASLD is characterized by hepatic steatosis (>5%) along with at least one cardiometabolic risk factor, no other causes of SLD, and minimal or no alcohol consumption. MASH, a more severe subtype of MASLD, is a progressive liver disease characterized by the presence of at least 5% hepatic steatosis, along with hepatocellular damage and inflammation. This condition can develop into advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), all of which are linked to significant morbidity and mortality. In the U.S., MASH ranks among the leading causes of HCC and is the second most common reason for liver transplantation after hepatitis C. Once MASH advances to clinically significant fibrosis (stages F2 and F3), the risk of serious clinical outcomes rises. Cardiovascular incidents are the primary cause of death in individuals with MASH, with non-liver cancers being the second leading cause.

Infectious Etiologies

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 the most commonly used histologic scoring system known as the Metavir system. The Metavir system includes scores for fibrosis (Table 1) and necroinflammatory activity (which refers to a combination of cellular events in which tissue necrosis is accompanied by an inflammatory response). This activity is graded as A0 = no activity, A1 = mild activity, A2 = moderate activity, and A3 = severe activity.

Hepatitis B Virus

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

Autoimmune Etiologies

Autoimmune liver diseases include autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). AIH is a rare, chronic inflammatory condition leading to liver parenchyma destruction by autoantibodies, commonly affecting women and associated with antinuclear antibodies, anti-smooth muscle antibodies, and hypergammaglobulinemia. PBC involves progressive autoimmune destruction of intrahepatic biliary channels, portal inflammation, and fibrosis, resulting in cholestatic jaundice, primarily in middle-aged women, with increased alkaline phosphatase. PSC, often linked to ulcerative colitis, is characterized by inflammation and fibrosis reducing intrahepatic and extrahepatic bile duct size, leading to bile duct strictures and cholestasis.

Genetic Etiologies

Alpha-1 antitrypsin deficiency, hereditary hemochromatosis, and Wilson disease are genetic etiologies of childhood onset of CLD. Alpha-1 antitrypsin deficiency is the most common. Hemochromatosis and Wilson disease are autosomal recessive conditions. Hemachromatosis involves HFE gene mutations causing excess iron deposition in the liver and Wilson disease involves ATP7B gene mutations causing excess copper buildup.

Other Etiologies

A wide range of drugs and drug classes can cause hepatotoxicity. Various vascular abnormalities, including but not limited to Budd-Chiari syndrome can also lead to advanced liver damage. Budd-Chiari syndrome is a rare vascular disorder caused by the obstruction of the hepatic venous outflow tract, which can be triggered by a hypercoagulable state resulting from specific medications. In 5-10% cases, the cause is unknown (cryptogenic or idiopathic).

Diagnosis, Monitoring and Surveillance

Biopsy for Chronic Liver Disease

The diagnosis of non-neoplastic liver disease can be 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 (see Table 1).

Accurate assessment of the degree of hepatic fibrosis and steatosis is essential in predicting prognosis and making treatment recommendations in individuals with CLD. While liver biopsy has long been the reference standard for assessing fibrosis and steatosis, the procedure is costly, invasive, and carries a small, but important, risk of complications. The frequency of biopsy-related complications varies based on operator experience, underlying comorbidities, size of the needle, number of needle passes, and hemostatic abnormalities such as thrombocytopenia and/or prolonged prothrombin time.

Noninvasive Alternatives to Liver Biopsy

Multiple noninvasive blood-based biomarkers and imaging technologies have been developed to reduce the need for liver biopsies. The term “noninvasive liver disease assessment(s)" (NILDA), has been used to describe these tests. They have been developed to determine the presence and severity of liver fibrosis, steatosis, and clinically significant portal hypertension. They offer safer and more repeatable assessments for disease progression and treatment response.

Multianalyte Assays

Multianalyte tests for CLD typically combine several blood-based biomarkers and clinical data (like age, sex, BMI) into a proprietary algorithm to assess steatosis, fibrosis, or liver cancer risk. These assays are often used in conjunction with imaging technologies to provide a comprehensive, non-invasive assessment of liver status. Most commercially available laboratory-developed biomarker tests for liver fibrosis are regulated under the Clinical Laboratory Improvement Amendments standards. These laboratory-developed tests (LDTs) have not been cleared or approved by the Food and Drug Administration (FDA).

The FDA cleared the ADVIA Centaur Enhanced Liver Fibrosis (ELF) test for marketing in the U.S. as a novel Class II medical device following a De Novo review (513(f)(2) pathway, DEN190056).

Table 2 lists the proprietary algorithm-based serum markers for liver fibrosis which are currently available in the U.S.:

Table 2. Multianalyte Assays

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 (TE), magnetic resonance elastography (MRE), acoustic radiation force impulse (ARFI) imaging, multiparametric magnetic resonance imaging (MRI), and real-time tissue elastography (RTE). Noninvasive imaging tests have been used in combination with multianalyte serum tests.

Table 3. Noninvasive Imaging Technologies

ARFI: Acoustic radiation Force Impulse; RTE: Real-time tissue elastography; TE: Transient elastography; MRE: Magnetic resonance elastography; MMRI: Multiparametric magnetic resonance imaging.

Current Clinical Care Pathway

CLD comprehensive treatment includes etiological management, lifestyle modifications, pharmacotherapy, nutritional support, prevention and management of complications, regular monitoring, and health education. For individuals with advanced liver disease, such as those experiencing cirrhosis or hepatic failure, liver transplantation may ultimately become the only effective option. Chronic hepatitis B or C can be treated with antivirals, such as lamivudine, entecavir, tenofovir (for HBV), or direct-acting antivirals like sofosbuvir or harvoni (for HCV).

There are two pharmacologic treatment options for MASH as adjuncts to lifestyle interventions. Lifestyle modification, including weight loss through a hypocaloric diet and physical activity, remains the cornerstone of MASH management and can reduce hepatic steatosis and improve insulin sensitivity.

For individuals with biopsy-confirmed MASH and fibrosis (≥F2), the FDA has granted accelerated approval for resmetirom (Rezdiffra, Madrigal Pharmaceuticals) and semaglutide (Wegovy, Novo Nordisk). These are prescribed in combination with diet and exercise for the treatment of adults with MASH and moderate to advanced liver fibrosis, (stages F2 to F3). Resmetirom, a liver-specific thyroid hormone receptor beta-agonist, is the first FDA-approved drug for non-cirrhotic MASH with moderate to advanced fibrosis, demonstrating histological and biochemical benefits. Resmetirom is administered orally once daily.

Semaglutide, a Glucagon-like peptide-1 (GLP-1) receptor agonist, is the second FDA-approved agent for MASH and is administered as a weekly subcutaneous injection.

POLICY

Multianalyte Assays

The FibroSURE multianalyte assay may be considered medically necessary for the evaluation of fibrosis staging in 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.

Noninvasive Imaging Technologies

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

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

The use of other noninvasive imaging, including but not limited to magnetic resonance elastography, multiparametric magnetic resonance imaging, acoustic radiation force impulse imaging, 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.

Increased fibrosis stage has important prognostic implications in nonalcoholic fatty liver disease (NAFLD) (now metabolic dysfunction-associated steatotic liver disease, MASLD, see Policy Description).

The American Association for the Study of Liver Diseases (AASLD) has developed an algorithm intended to be used by clinicians in need of a readily available and simple decision support tool for liver disease assessment (see below). The AASLD recommends that fibrosis staging begin with nonproprietary blood-based tests because of their wide availability and performance compared to proprietary tests. Nonproprietary tests include the Fibrosis-4 (FIB-4) Index, and NAFLD/NASH fibrosis score (NFS) which are used as initial blood-based tests to rule-out advanced fibrosis. The fibrosis 4 (FIB-4) Index calculator estimates the likelihood of advanced liver fibrosis (scarring) by combining a patient's age with aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count values. A low FIB-4 score (typically <1.3 or <1.45) suggests a low risk of advanced fibrosis, while a high score (typically >2.67 or >3.25) indicates a high risk and may warrant further assessment, potentially a liver biopsy.

The NFS score is calculated using a formula that considers the following factors: age, body mass index (BMI), diabetes status, and blood test results (AST/ALT ratio, albumin, platelet count). The NFS is interpreted as follows:

• Score <-1.455: Low risk of advanced fibrosis

• Score between -1.455 and 0.676: Indeterminate risk

• Score >0.676: High risk of advanced fibrosis

The AASLD Practice Guidelines Committee commissioned a diverse group of experts across multiple disciplines in the field of adult and pediatric liver disease to develop guidelines and guidance statements along with a systematic review covering blood-based noninvasive tests to address specific clinically focused questions. Of these tests, FIB-4 was considered to have superior performance, particularly for the identification of F3-4 stages of fibrosis, which is the spectrum of fibrosis for which the tests were designed. NFS was considered an equivalent to FIB-4 in patients with NAFLD in the assessment of advanced fibrosis. FIB-4 thresholds of ≤1.30 and ≥2.67, and NFS thresholds of ≤-1.455 and ≥0.676, have been proposed as having higher predictive values for F3-4 in NAFLD. The AASLD recommends that in the appropriate clinical setting (i.e., low pre-test probability), both tests should suffice to rule out significant/advanced fibrosis.

Confirmatory testing (secondary assessment) such as noninvasive imaging technologies should be performed for patients with values between the lower and upper thresholds of these tests. Patients with FIB-4 scores less than 1.3 are unlikely to have advanced fibrosis. High-risk individuals, such as those with type 2 diabetes, medically complicated obesity, family history of cirrhosis, or more than mild alcohol consumption, should be screened for advanced fibrosis.

The AASLD Practice Guidelines Committee made an ungraded statement that in adults with CLD, either ultrasound-based elastography methods or magnetic resonance elastography (MRE) can be utilized to stage fibrosis. Depending on local availability and expertise, it is reasonable to perform MRE as an investigation when concomitant cross-sectional imaging is needed or for patients in whom the accuracy of US-based elastography might be compromised.

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.

04/01/2026: Code Reference section updated to add new CPT code 0624U.

07/01/2026: Policy description extensively revised. Added information regarding staging of fibrosis across multiple etiologies, multianalyte assays, and noninvasive imaging technologies. Policy statement revised to state that the FibroSURE multianalyte assay may be considered medically necessary for the evaluation of fibrosis staging in individuals with chronic liver disease. It previously stated: A single FibroSURE multianalyte assay may be considered medically necessary for the evaluation of individuals with chronic liver disease. Policy Guidelines updated regarding fibrosis staging. Code Reference section updated to add new CPT code 1043T as investigational.

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

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