921 Form

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Medical Policy Noninvasive Techniques for the Evaluation and Monitoring of Patients with Chronic Liver Disease Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 921 BCBSA Reference Number: 2.04.41 (For Plan internal use only) NCD/LCD: N/A
Related Policies
None Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

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 (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 noninvasive imaging, including but not limited to, acoustic radiation force impulse imaging or real-time tissue elastography, is considered INVESTIGATIONAL for the evaluation or monitoring of individuals with chronic liver disease.

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Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) Prior authorization is not required. Commercial PPO and Indemnity Prior authorization is not required. Medicare HMO BlueSM Prior authorization is not required. Medicare PPO BlueSM Prior authorization is not required. CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue: CPT Codes CPT codes: Code Description 0002M Liver disease, 10 biochemical assays (ALT, A2-macroglobulin, apolipoprotein A1, total bilirubin, GGT, haptoglobin, AST, glucose, total cholesterol and triglycerides) utilizing serum, prognostic algorithm reported as quantitative scores for fibrosis, steatosis, and alcoholic steatohepatitis (ASH) 0003M Liver disease, 10 biochemical assays (ALT, A2-macroglobulin, apolipoprotein A1, total bilirubin, GGT, haptoglobin, AST, glucose, total cholesterol and triglycerides) utilizing serum, prognostic algorithm reported as quantitative scores for fibrosis, steatosis, and nonalcoholic steatohepatitis (NASH) 81596 Infectious disease, chronic hepatitis C virus (HCV) infection, six biochemical assays (ALT, A2-macroglobulin, apolipoprotein A-1, total bilirubin, GGT, and haptoglobin) utilizing serum, prognostic algorithm reported as scores for fibrosis and necroinflammatory activity in liver 91200 Liver elastography, mechanically induced shear wave (eg, vibration), without imaging, with interpretation and report

The following ICD Diagnosis Codes are considered medically necessary when submitted with the CPT codes above if medical necessity criteria are met:

ICD-10 Diagnosis Codes

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ICD-10-CM Diagnosis codes: Code Description B18.0 Chronic viral hepatitis B with delta-agent B18.1 Chronic viral hepatitis B without delta-agent B18.2 Chronic viral hepatitis C B18.8 Other chronic viral hepatitis B18.9 Chronic viral hepatitis, unspecified B19.0 Unspecified viral hepatitis with hepatic coma B19.10 Unspecified viral hepatitis B without hepatic coma B19.11 Unspecified viral hepatitis B with hepatic coma B19.20 Unspecified viral hepatitis C without hepatic coma B19.21 Unspecified viral hepatitis C with hepatic coma B19.9 Unspecified viral hepatitis without hepatic coma 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 K70.41 Alcoholic hepatic failure with coma K70.9 Alcoholic liver disease, unspecified K71.0 Toxic liver disease with cholestasis K71.10 Toxic liver disease with hepatic necrosis, without coma K71.11 Toxic liver disease with hepatic necrosis, with coma K71.2 Toxic liver disease with acute hepatitis 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 K72.00 Acute and subacute hepatic failure without coma K72.01 Acute and subacute hepatic failure with coma K72.10 Chronic hepatic failure without coma K72.11 Chronic hepatic failure with coma K72.90 Hepatic failure, unspecified without coma K72.91 Hepatic failure, unspecified with 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 K73.8 Other chronic hepatitis, not elsewhere classified K73.9 Chronic hepatitis, unspecified K74.00 Hepatic fibrosis, unspecified

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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 K75.0 Abscess of liver K75.1 Phlebitis of portal vein K75.2 Nonspecific reactive hepatitis K75.3 Granulomatous hepatitis, not elsewhere classified K75.4 Autoimmune hepatitis K75.81 Nonalcoholic steatohepatitis (NASH) K75.89 Other specified inflammatory liver diseases K75.9 Inflammatory liver disease, unspecified K76.0 Fatty (change of) liver, not elsewhere classified K76.1 Chronic passive congestion of liver K76.2 Central hemorrhagic necrosis of liver K76.3 Infarction of liver K76.4 Peliosis hepatis K76.5 Hepatic veno-occlusive disease K76.6 Portal hypertension K76.7 Hepatorenal syndrome K76.81 Hepatopulmonary syndrome K76.82 Hepatic encephalopathy K76.89 Other specified diseases of liver K76.9 Liver disease, unspecified K77 Liver disorders in diseases classified elsewhere

According to the policy statement above, the following CPT codes are considered investigational for the conditions listed for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes: Code Description 76981 Ultrasound, elastography; parenchyma (eg, organ) 76982 Ultrasound, elastography; first target lesion 76983 Ultrasound, elastography; each additional target lesion (List separately in addition to code for primary procedure) 81517 Liver disease, analysis of 3 biomarkers (hyaluronic acid [HA], procollagen III amino terminal peptide [PIIINP], tissue inhibitor of metalloproteinase 1 [TIMP-1]), using immunoassays, utilizing serum, prognostic algorithm reported as a risk score and risk of liver fibrosis and liver-related clinical events within 5 years

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DESCRIPTION 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.1,

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).2,

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).3,4,

Table 1. Staging of Fibrosis across Multiple Etiologies* Significant Fibrosis Advanced Fibrosis Etiology 0 FI F2 F3 F4 • ALD • No fibrosis or portal fibrosis • Expansive periportal fibrosis • Bridging fibrosis • Cirrhosis • N/A • MASLD • [Brunt- Kleiner • system] • No fibrosis • 1A: delicate perisinusoidal 1B: dense perisinusoidal 1C: portal- only fibrosis • Perisinusoidal and portal/ periportal fibrosis • Bridging fibrosis • Cirrhosis

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• Viral and Autoimmune Hepatitis • No fibrosis • Enlarged, fibrotic portal tracts (Fibrous portal expansion) • Periportal or portal-portal septa but intact architecture • Fibrosis with architectural distortion but no obvious cirrhosis (Bridging fibrosis) • Cirrhosis • PBC and PSC • N/A • N/A • N/A • Bridging fibrosis • Cirrhosis • Various etiologies [Metavir system] • No fibrosis • Stellate enlargement of portal tract but without septa formation • Enlargement of portal tract with rare septa formation • Numerous septa without cirrhosis • Cirrhosis

• Adapted from American Association for the Study of Liver Diseases (AASLD) Practice Guidelines (2025)3,4, 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.5,6, 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.7,2, 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.8, 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.9,10,

  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

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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).11,

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.3,

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.3, They offer safer and more repeatable assessments for disease progression and treatment response.

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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 Test (Manufacturer) Description Regulatory Status FibroSURE (LabCorp) • 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; it is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and alcoholic steatohepatitis. The test has been available in Europe under the name AshTest™ (BioPredictive); the test is exclusively offered by LabCorp in the U.S. as ASH FibroSURE.
• HCV FibroSURE uses a combination of 6 serum biochemical markers of liver function plus age and sex in a patented algorithm to generate a measure of fibrosis and inflammation activity in the liver that corresponds to the Metavir system (Table 1). These markers are combined using a linear regression equation to produce a score between 0 and 1, with higher values corresponding to more severe disease. The test has been clinically available in Europe under the name FibroTest since 2003. It is exclusively offered by LabCorp in the U.S. as HCV FibroSURE. • NASH FibroSURE (NASH Test) uses a proprietary algorithm of the same 10 biochemical markers (as the ASH test) 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 test has been available in Europe under the name NashTest (BioPredictive); the test is exclusively LDTs

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offered by LabCorp in the U.S. as NASH FibroSURE.

FIBROSpect II (Prometheus Laboratories) • FIBROSpect II uses a combination of 3 serum markers to assess the degree of liver fibrosis: hyaluronic acid; tissue inhibitor of metalloproteinase 1; and alpha- 2-macroglobulin. These markers are combined using a logistic regression algorithm to generate a index score, ranging from 1 to 100 (or sometimes reported between 0 and 1), with higher scores indicating more severe disease.

LDTs OWLiver panel (CIMA Sciences in partnership with Luxor Scientific) • The OWLiver test is a serum test for detecting MASLD, MASH with moderate or no fibrosis (F0-F1), and “at-risk" MASH (with significant fibrosis F≥2). The test uses two algorithms, OWLiver-MASH and MASEF score, which combine a panel of 16 and 12 lipid biomarkers in tandem with BMI, AST, and ALT using multivariable logistic regression analysis. This provides a predicted probability score (ranging from 0 to 1) of MASH (OWLiver-MASH) or MASH with significant fibrosis (F≥2) (MASEF Score).

LDTs Enhanced Liver Fibrosis (Siemens Healthineers) • The Enhanced Liver Fibrosis (ELF) test uses a proprietary algorithm of markers to produce a score based on 3 components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1. The test stratifies risk for developing cirrhosis or other liver- related events based on the following ranges: <9.80 (lower risk) and ≥11.30 (higher risk). Specific ELF thresholds are used in clinical pathways to guide further assessment and management in NAFLD (MASLD): <7.7 and 9.8 (low and high thresholds). • In August 2021, the ADVIA Centaur Enhanced Liver Fibrosis (ELF) test (Siemens Healthcare) was cleared by the FDA for marketing as a Class II novel medical device after the De Novo review (513(f)(2)) pathway (DEN190056). o In 2018, the test was granted a first Breakthrough Device Designation (BDD) for predicting disease progression in patients with advanced fibrosis due to NAFLD. o In 2023, the ELF test was granted a second BDD to aid in the identification of advanced fibrosis (≥F3) and cirrhosis (F4) in patients with NAFLD.

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Non-invasive Imaging Technologies

Noninvasive imaging technologies to detect liver fibrosis or cirrhosis among patients with CLD are being evaluated as alternatives to liver biopsy. The noninvasive imaging technologies for review are 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. Non-invasive Imaging Technologies Technology Description Device (Vendor, FDA Decision Date, 510(k) Number) Ultrasound Technologies ARFI imaging (shear wave elastography) • 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 encompasses two related techniques: point shear wave elastography (pSWE), which assesses regions of interest measuring 10×5 mm2, and two-dimensional shear wave elastography (2D-SWE), which assesses more than one region of interest in rapid succession to decrease sampling error. ARFI elastography can be performed at the same time as a liver sonographic evaluation, even in patients with a significant amount of ascites. • pSWE: Acuson S2000 Virtual Touch (Siemens AG, 2008, K072786). • 2D-SWE: ElastQ Imaging shear wave elastography (Phillips, 2017, K163120). 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 ultrasound images in real-time. Challenges in the use of this test are 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. RTE can be performed in patients with ascites or inflammation. This technology does not perform as well in severely obese individuals.

• HI VISION™ Preirus Diagnostic Ultrasound Scantier (Hitachi Medical Systems America, 2010, K093466).

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TE • TE 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. Cut-off values, expressed in kilopascals (kPa), vary by disease and patient population, but generally range from >7-8 kPa for significant fibrosis (≥F2 or F3) to >10- 17.6 kPa for cirrhosis (F4). • TE does not perform as well in patients with ascites, higher BMI, or narrow intercostal margins. Although this test may be used to measure fibrosis, it does not provide information on inflammatory activity and steatosis, nor is it accurate during acute hepatitis or hepatitis exacerbations.

• AIXPLORER Ultrasound System (SuperSonic Imagine, 2009, K091970). • FibroScan (EchoSens, 2013, K123806).

Magnetic Resonance Technologies MRE • MRE 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. • MRE has several advantages over ultrasound elastography, including the ability to analyze larger liver volumes, liver volumes of obese patients or patients with ascites, and viscoelasticity using a 3-dimensional displacement vector.

• Magnetic Resonance Elastography (MRE) (Resoundant, 2009, K083421; available by GE Healthcare, Siemens Healthineers, Philips)

MMRI • MMRI 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 is a magnetic resonance diagnostic device software application (Perspectum, 2015, K143020).

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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).12,

There are two pharmacologic treatment options for MASH as adjuncts to lifestyle interventions.13,14,15, 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.

Summary Description Noninvasive techniques to monitor liver fibrosis are being investigated as alternatives to liver biopsy in patients with chronic liver disease. There are 2 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.

Summary of Evidence

Multianalyte Serum Assays For individuals who have chronic liver disease (CLD) who receive FibroSURE serum panels, the evidence includes systematic reviews of more than 30 observational studies (>5000 patients). Relevant outcomes are test validity, morbid events, and treatment-related morbidity. FibroSURE has been studied in populations with viral hepatitis, nonalcoholic fatty liver disease (NALFD)/metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-associated liver disease (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 patient has severe fibrosis or cirrhosis, FibroSURE results 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 randomized controlled trials (RCTs) that showed the efficacy of hepatitis C virus (HCV) treatments, which in turn demonstrated that the test can identify patients who would benefit from therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have CLD who receive multianalyte serum assays for liver function assessment other than FibroSure, such as the Enhanced Liver Fibrosis (ELF) test and OWLiver panel, the evidence includes observational studies and systematic reviews. The ELF test shows high sensitivity but lower specificity for detecting advanced fibrosis in NAFLD/MASLD, especially at lower thresholds. The positive

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predictive value of the test improves with higher thresholds and greater disease prevalence. A systematic review conducted in support of the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines (2024) reported conflicting data on the diagnostic accuracy of ELF compared with nonproprietary blood-based tests such as the Fibrosis-4 (FIB-4) Index, and NAFLD/NASH fibrosis score (NFS) for the detection of fibrosis in NAFLD. The AASLD noted that in community-based and other low prevalence cohorts, blood-based noninvasive tests are useful for excluding advanced fibrosis with high negative predictive value but require additional noninvasive tests to improve their positive predictive value. A multicenter cross‐sectional study demonstrated high accuracy of the OWLiver panel for diagnosing MASH and advanced fibrosis in patients with obesity and type 2 diabetes, with consistent results across obesity levels and diabetes control. Further studies comparing the OWLiver panel to nonproprietary tests in larger and more diverse patient populations is necessary to confirm these findings. There is no direct evidence that either of these multianalyte serum assays improve health outcomes; further, it is not possible to construct a chain of evidence for clinical utility due to the lack of sufficient evidence on clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Noninvasive Imaging 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 patients). Relevant outcomes are test validity, morbid events, and treatment-related morbidity. Transient elastography (FibroScan) has been studied in populations with viral hepatitis, NALFD, and ALD. There are varying cutoffs for positivity. Failures of the test are not uncommon, particularly for those with high body mass index, but these failures often went undetected in analyses of the validation studies. Given these limitations and the imperfect reference standard, it can be difficult to interpret performance characteristics. However, for the purposes of deciding whether a patient has severe fibrosis or cirrhosis, the FibroScan results provide data sufficiently useful to determine therapy. In fact, FibroScan has been used as an alternative to biopsy to establish eligibility regarding the presence of fibrosis or cirrhosis in the participants of several RCTs. These trials showed the efficacy of HCV treatments, which in turn demonstrated that the test can identify patients who would benefit from therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

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

For individuals who have chronic liver disease who receive noninvasive radiologic methods other than transient elastography or multiparametric magnetic resonance imaging (MMRI) for liver fibrosis measurement, the evidence includes systematic reviews of observational studies and a comparative study with 5-year follow up. Relevant outcomes are test validity, morbid events, and treatment-related morbidity. Other radiologic methods (eg, magnetic resonance elastography [MRE], real-time transient elastography [RTE], acoustic radiation force impulse imaging [ARFI] imaging) may have similar performance for detecting significant fibrosis or cirrhosis. A systematic review conducted to support the AASLD Practice Guidelines (2024) reported that liver-stiffness measurement from MRE and shear wave elastography/ARFI (in addition to TE) shows high accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. In the comparative study, ARFI elastography was found to be at least as effective as liver histology in predicting

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liver-related survival, and was superior to both histology and the FIB-4 score in predicting certain liver- related complications. 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; further, it is not possible to construct a chain of evidence for clinical utility due to the lack of sufficient evidence on clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 12/2025 Annual policy review. Policy updated with literature review through September 22, 2025; references added. Substantive policy statement edits; intent unchanged. 1/2025 Annual policy review. Policy updated with literature review through September 27, 2024; references added. Policy statements unchanged. 1/2024 Annual policy review. Description, summary, and references updated. Policy statements unchanged. Clarified coding information. 3/2023 Clarified coding information. 1/2023 Annual policy review. References updated. Minor editorial refinements to policy statements; intent unchanged. 1/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 6/2020 Clarified coding information. 1/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged. Clarified coding information.
12/2019 Code 76391 Magnetic resonance (eg, vibration) elastography removed. Effective 12/9/2019.
1/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. Clarified coding information.
1/2018 Annual policy review. New references added. 10/2017 Clarified coding information. 5/2017 Annual policy review. New medically necessary and investigational indications described. New references added. Effective 5/1/2017. 8/2015 Annual policy review. 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.”
New investigational indications described. Clarified coding information. Effective 8/1/2015. 9/2014 Annual policy review. New references added. 10/2013 Annual policy review. New references added. 3/2013 New policy describing non-coverage. Effective 3/1/2013.
Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

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