CAM 20441

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

Category:Laboratory   Last Reviewed:October 2020
Department(s):Medical Affairs   Next Review:October 2021
Original Date:March 2005    

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

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

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

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

Hepatic fibrosis is associated with a cycle of extracellular matrix deposition and degradation. Biomarkers of extracellular matrix turnover are used to directly assess fibrosis and theoretically to monitor progression or regression (Valva, Rios, De Matteo, & Preciado, 2016). These markers include several glycoproteins, members of the collagen family, collagenases and their inhibitors, and a number of cytokines involved in the fibrogenic process (Valva et al., 2016), individually as well as in panel combinations (Parikh, Ryan, & Tsochatzis, 2017).

Regulatory Status
A search for “fibrosis” on the FDA website on August 7, 2019, did not yield any results relevant to hepatic conditions. Although several of these panels are patented, none are FDA approved.  Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy
Transient elastography (FibroScan) imaging may be considered MEDICALLY NECESSARY for the evaluation of patients with chronic liver disease.

Transient elastography (FibroScan) imaging is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for monitoring of patients with chronic liver disease.  

The use of multianalyte assays with algorithmic analysis (e.g., FibroTest, FibroSure, ELF) to distinguish hepatic cirrhosis is considered MEDICALLY NECESSARY  for individuals with one of the following conditions:

  1. Hepatitis C
  2. Hepatitis B
  3. Non-alcoholic fatty liver disease (NAFLD)

Multianalyte assays with algorithmic analyses, such as NASH FibroSure, is considered NOT MEDICALLY NECESSARY for non-alcoholic steatohepatitis (NASH).

Multianalyte assays with algorithmic analyses (e.g., FibroTest, FibroSure, NASH FibroSure) to diagnose, evaluate, or monitor fibrosis is considered NOT MEDICALLY NECESSARY in all other circumstances.

The use of the following serum biomarkers in immunoassays and/or immunohistochemistry assays to diagnose, evaluate, or monitor hepatic fibrosis of patients with chronic liver disease is considered investigational and/or unproven and is therefore considered NOT MEDICALLY NECESSARY:

    1. Signal-induced proliferation-associated 1 like 1 (SIPA1L1)
    2. microRNA (miRNA or miR) analysis, including but not limited to, the following:
      1. microRNA-21 (miRNA-21 or miR-21)
      2. miRNA-29a (miR-29a)
      3. miRNA-122 (miR-122)
      4. miRNA-221 (miR-221)
      5. miRNA-222 (miR-222)
    3. Chitinase 3-like 1 (CHI3L1)
    4. Hyaluronic acid
    5. Type III procollagen (PCIII)
    6. Type IV collagen
    7. Laminin
    8. Plasma caspase-generated cytokeratin-18
    9. Micro-fibrillar associated glycoprotein 4 (MFAP4)

Magnetic resonance elastography liver is considered MEDICALLY NECESSARY in the following circumstances:

Non-alcoholic fatty liver disease (NAFLD) in high risk (for cirrhosis) populations:

  • Advanced age (65 years old or greater)
  • Obesity (BMI 30 or higher)
  • Diabetes
  • ALT >2X upper limit of normal

For NAFLD in low risk populations (e.g., signs of fatty liver found on imaging only, without the above-noted risk factors), MRE would be considered investigational and/or unproven and therefore NOT MEDICALLY NECESSARY.

The use of other noninvasive imaging, including, but not limited to, acoustic radiation force impulse imaging (ARFI; e.g., Acuson S2000) or real-time tissue elastography, is considered investigational and/or unproven therefore is considered NOT MEDICALLY NECESSARY for the evaluation or monitoring of patients with chronic liver disease.

Rationale
MULTIPLE NONINVASIVE TESTS
As mentioned in the Background, liver biopsy is an imperfect reference standard. There is a high rate of sampling error in biopsy, which can lead to underdiagnosis of liver disease.1,2 These errors will bias estimates of performance characteristics of the noninvasive tests to which it is compared, and therefore such errors must be considered in apprising the body of evidence. Mehta et al (2009) estimated that—even under the best scenario where sensitivity and specificity of liver biopsy are 90%, and the prevalence of significant disease (increased liver fibrosis, scored as Metavir ≥ F2) is 40%—a perfect alternative marker would have calculated area under the receiver operating characteristic (AUROC) curve of 0.90.3 Therefore, effectiveness of alternative technologies may be underestimated. In fact, when the accuracy of biopsy is presumed to be 80%, a comparative technology with an AUROC curve of 0.76 may actually have an AUROC curve of 0.93 to 0.99 for diagnosing true disease.

Due to the large number of primary studies published on this topic, this evidence review focuses on systematic reviews when available. The validation of multiple noninvasive tests will be assessed individually in the following sections. In this section, systematic reviews that compare several noninvasive tests will be discussed. Although options exist for performing systematic reviews with imperfect reference standards,4 the majority of available reviews on this topic did not use any correction for the imperfect reference.

A systematic review by Crossan et al (2015) was performed for the National Institute for Health Research.5 The first objective of the review was to determine the diagnostic accuracy of different noninvasive liver tests compared with liver biopsy in the diagnosis and monitoring of liver fibrosis and cirrhosis in patients with hepatitis C virus (HCV), hepatitis B virus (HBV), nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Also included in the Crossan et al systematic review were 302 publications and presentations from 1998 to April 2012. Patients with HCV were the most common population included in the studies while patients with ALD were the least common. FibroScan and FibroTest were the most commonly assessed tests across liver diseases. Aminotransferase to platelet ratio index (APRI) was also widely assessed in HBV and HCV but not in NAFLD or ALD. The estimates of diagnostic accuracy for each test by disease (as determined by Crossan et al) are discussed in further detail in the following sections. Briefly, for diagnosing significant fibrosis (stage ≥ F2) in HCV, the summary sensitivities and specificities were: FibroScan, 79% and 83%; FibroTest, 68% and 72%; APRI (low cutoff), 82% and 57%; acoustic radiation force impulse imaging (ARFI), 85% and 89%; HepaScore, 73% and 73%, FIBROSpect II, 78% and 71%; and FibroMeter, 79% and 73%, respectively. For diagnosing advanced fibrosis in HBV, the summary sensitivities and specificities were: FibroScan, 71% and 84%; FibroTest, 66% and 80%, respectively. There are no established or validated cutoffs for fibrosis stages across the diseases for most tests. For FibroTest, established cutoffs exist but were used inconsistently across studies. Test failures or reference standard(s) were frequently not captured in analyses. Most populations included in the studies were from tertiary care settings who have more advanced disease than the general population, which would overestimate the prevalence of the disease and diagnostic accuracy. These issues likely cause overestimates of sensitivities and specificities. The quality of the studies was generally rated as poor, with only 1.6% receiving a high-quality rating.

In 2016, Houot et al reported on a systematic review funded by BioPredictive, the manufacturer of FibroTest.6 Reviewers included 71 studies published between January 2002 to February 2014 with over 12,000 participants with HCV and HBV comparing the diagnostic accuracy of FibroTest, FibroScan, APRI, and FIB4 index. Reviewers included studies that directly compared the tests and calculated median differences in the AUROC using Bayesian methods. There was no evaluation of the methodologic quality of the included studies. The Bayesian difference in AUROC curve for significant fibrosis (stage ≥ F2) between FibroTest and FibroScan was based on 15 studies and estimated to be 0.06 (95% credible interval [CrI], 0.02 to 0.09) favoring FibroTest. The difference in AUROC curve for cirrhosis for FibroTest vs FibroScan was based on 13 studies and estimated to be 0.00 (95% CrI, 0.04 to 0.04). The difference for advanced fibrosis between FibroTest and APRI was based on 21 studies and estimated to be 0.05 (95% CrI, 0.03 to 0.07); for cirrhosis, it was based on 14 studies and estimated to be 0.05 (95% CrI, 0.00 to 0.11), both favoring FibroTest. 

Fibrosis is a wound healing response in which damaged regions are encapsulated by an extracellular matrix. This is common in individuals with chronic liver injury but may be seen in other organs such as the kidneys or lungs. Chronic liver injury may be caused by numerous conditions, such as hepatitis, and progressive fibrosis may lead to cirrhosis (Friedman, 2018). Liver biopsy remains the gold standard for evaluation of chronic liver disease to monitor treatment and disease progression. However, this invasive procedure has several drawbacks, including pain, bleeding, inaccurate staging due to sampling error, and variability of biopsy interpretation (Chin, Pavlides, Moolla, & Ryan, 2016). Serum biomarkers, such as the aspartate aminotransferase (AST) to platelet ratio (APRI), have been proposed as measures of hepatic fibrosis assessment, and numerous panels exist (Curry & Afdhal, 2018).

These markers (and corresponding panels) may be categorized as “direct” or “indirect”. Direct markers of fibrosis evaluate extracellular matrix turnover, and indirect markers signify changes in hepatic function. Direct biomarkers may be further subdivided by markers associated with matrix deposition, matrix degradation, or cytokines (and chemokines) associated with fibrogenesis. Procollagen I peptide, procollagen III peptide, type I collagen, type IV collagen, YKL-40 (chondrex), laminin, and hyaluronic acid, MMP-2, TIMP-1, -2, TGF-beta, TGF-alpha, and PDGF have all been proposed as direct measures of fibrosis. Indirect markers include serum aminotransferase levels, platelet count, coagulation parameters, gamma-glutamyl transferase (GGT), total bilirubin, alpha-2-macroglobulin, and alpha-2-globulin (haptoglobin) (Curry & Afdhal, 2018). Other markers have been investigated to be used independently or as part of these panels.ffThe human microfibrillar-associated protein 4 (MFAP4) is located in extracellular matrix fibers and plays a role in disease-related tissue remodeling. Bracht et al evaluated the “potential” of MFAP4 as a biomarker for hepatic fibrosis. 542 patients were included, and the authors focused on differentiation of no to moderate (F0–F2) and severe fibrosis stages and cirrhosis (F3 and F4). In the “leave-one-out cross validation”, a sensitivity of 85.8% and specificity of 54.9% was observed and the multivariate model yielded 81.3 % sensitivity and 61.5 % specificity. The authors suggested that “the combination of MFAP4 with existing tests might lead to a more accurate non-invasive diagnosis of hepatic fibrosis and allow a cost-effective disease management in the era of new direct acting antivirals” (Bracht et al., 2016).

Plasma caspase-generated cytokeratin-18 fragments (CK-18) have been proposed as a biomarker in the diagnosis and staging of non-alcoholic steatohepatitis (NASH). Cusi et al (2014) studied the clinical value of CK-18. The authors studied the adipose tissue, liver, and muscle insulin resistance of 424 patients as well as liver fat (n = 275) and histology (n = 318). The authors found that median CK-18 were elevated in patients with vs. without NAFLD (209 U/L vs. 122 U/L) or with vs. without NASH (232 U/L vs. 170 U/L). The CK-18 area under curve to predict NAFLD, NASH or fibrosis were 0.77, 0.65, and 0.68, respectively. The overall sensitivity/specificity for NAFLD, NASH and fibrosis were 63%/83%, 58%/68% and 54%/85%, respectively. CK-18 correlated most strongly with ALT (r=0.57) and adipose tissue IR (insulin-suppression of FFA: r=-0.43), but not with ballooning, BMI, metabolic syndrome or T2DM. The authors concluded, “Plasma CK-18 has a high specificity for NAFLD and fibrosis, but its limited sensitivity makes it inadequate as a screening test for staging NASH. Whether combined as a diagnostic panel with other biomarkers or clinical/laboratory tests may prove useful requires further study (Cusi et al., 2014).”

Likewise, Chitinase 3-like 1 (CHI3L1) has been proposed to be a better serum biomarker than hyaluronic acid, type III procollagen, type IV collagen, and laminin.  CHI3L1 is preferentially expressed in hepatocytes over any other body tissue.  Huang and colleagues investigated CHI3L1 in 98 patients with hepatitis B. The authors reported that CHI3L1 can be used to differentiate between early stages of liver fibrosis (S0-S2) from late stages (S3-S4) “with areas under the ROC curves (AUCs) of 0.94 for substantial (S2, S3, S4) fibrosis and 0.96 for advanced (S3, S4) fibrosis” (Huang et al., 2015).

MiRNA sequences have also been proposed as a marker of liver function. MiRNA sequences often have roles in gene regulation and other cellular processes, so changes in these sequences may indicate a liver condition (Tendler, 2018). For example, Abdel-el et al investigated miRNA’s association with HCV patients. 42 patients with HCV and early-stage fibrosis, 45 patients with HCV and late-stage fibrosis, and 40 healthy controls were examined and the expression patterns of 5 miRNA sequences (miR-16, miR-146a, miR-214-5p, miR-221, and miR-222) were measured. The authors found miRNA-222 to have the highest sensitivity and specificity for both fibrosis groups, and all mi-RNA sequences except miRNA-214-5p were significantly upregulated in fibrosis. MiRNA-221 was also found to have significant positive correlations with miRNA-16 and miRNA-146a. The authors concluded that “the high sensitivity and specificity of miRNA-222 and miRNA-221 in late-stage fibrosis indicate promising prognostic biomarkers for HCV-induced liver fibrosis (Abdel-Al et al., 2018).

Multiple biomarkers may be combined into a panel. Panels may include a combination of direct markers, indirect markers, or markers from both categories. The most studied panels are the aspartate aminotransferase (AST) to platelet ratio (APRI), FibroTest/FibroSure, and Hepascore; although many more exist. FibroTest/FibroSure incorporates alpha-2-macroglobulin, alpha-2-globulin (haptoglobin), gamma globulin, apolipoprotein A1, GGT, and total bilirubin, age and sex. HepaScore measures bilirubin, GGT, hyaluronic acid, alpha-2-macroglobulin, age, and sex. These panels have demonstrated some promising results, but Curry and Afdhal note that indeterminate outcomes are common. Furthermore, they state that no singular panel has emerged as the standard of care (Curry & Afdhal, 2018).

Many combinations of biomarkers and even combinations of panels exist. For example, FibroMax combines FibroTest, SteatoTest, NashTest, ActiTest, and AshTest on the same result sheet and provides a more comprehensive estimation of the liver injury. This test measures 10 biomarkers which are as follows:  Gamma-GT, total bilirubin, alpha-2-macroglobulin, apolipoprotein A1, haptoglobin, alanine aminotransferase (ALT), AST Transaminase, triglycerides, cholesterol, and fasting glucose (BioPredictive, 2019). Fouad et al (2013) found that in 44 patients that FibroMax results were positively correlated with viral load by quantitative polymerase chain reaction and histopathological findings. Body mass index was significantly higher in steatotic patients and was significantly associated with the results on FibroMax.

Clinical Validity and Utility
Berends et al performed a study assessing FibroTest’s ability to detect methotrexate (MTX)-induced hepatic fibrosis. 24 psoriasis patients that underwent a liver biopsy were included, and FibroTest identified 83 percent of the patients who had significant fibrosis. The authors suggested FibroTest may be used as part of monitoring MTX-induced fibrosis (Berends et al., 2007).

Kwok et al (2014) performed a meta-analysis of non-invasive assessments of NASH. The authors identified 9 studies for transient elastography (TE) and 11 for cytokeratin‐18 (CK-18). The pooled sensitivities and specificities for TE to diagnose F ≥ 2, F ≥ 3, and F4 disease were 79% and 75%, 85% and 85%, and 92% and 92%, respectively. CK-18 was found to have a pooled sensitivity of 66% and specificity of 82% in diagnosing NASH. The authors concluded that “At present, serum tests and physical measurements such as TE come close as highly accurate non‐invasive tests to exclude advanced fibrosis and cirrhosis in NAFLD patients. CK18 has moderate accuracy in diagnosing NASH, while other biomarkers have not been extensively studied (Kwok et al., 2014).”

Gao et al (2018) compared aspartate amino transferase–to-platelet ratio index (APRI), the Fibrosis-4 index (FIB-4), transient elastography (TE), and two-dimensional (2D) shear-wave elastography (SWE). 402 patients with chronic hepatitis B were included. 2D-SWE was found to have the highest area under the curve (AUC), with 0.87 compared to APRI’s 0.70, TE’s 0.80, and FIB-4’s 0.73.

Dong et al (2018) compared the performance of several biomarkers (serum hyaluronan (HA), procollagen type III N-terminal peptide (PIIINP), type IV collagen (IVC), laminin (LN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)) to transient elastography (FibroScan). 70 patients with hepatitis B underwent a liver biopsy. Fibrosis was found in 24 patients. The correlation of serum levels with fibrosis stage are as follows: 0.468 (HA), 0.392 (PIIINP), 0.538 (IVC), 0.213 (LN), 0.350 (ALT), 0.375 (AST). The authors found that the combination of all five biomarkers yielded a superior diagnostic performance (area under curve: 0.861) compared to all five alone.

A pilot study of the FM-fibro index (Itoh et al., 2018)  was performed with 400 patients enrolled, and the FM-fibro index, CA‐fibro index, and European Liver Fibrosis panel (ELF) were compared with respect to estimating prognosis of patients with NAFLD. Three separate biomarkers comprise the FM-fibro index, type IV collagen 7S, hyaluronic acid, and vascular cell adhesion molecule‐1. The area under the curve was 0.7093 for the CA-fibro index, 0.7245 for ELF, and 0.7178 (type IV collagen 7S)/0.7095 (hyaluronic acid)/0.7065 (vascular cell adhesion molecule‐1). The sensitivity and specificity of the FM-fibro index for predicting NASH-related fibrosis was 0.5359/0.5210/0.4641 and 0.8333/0.8182/0.8788, respectively. The accuracy of the FM-fibro index was not significantly different from that of the CA-fibro index and the ELF panel.

Patel et al (2018) performed a retrospective study focusing on fibrosis scoring systems to identify NAFLD. 329 patients (296 NAFLD, 33 controls) were included.  The following indices were studied: “NAFLD fibrosis score (NFS), fibrosis-4 calculator (FIB-4), aspartate aminotransferase-to-alanine aminotransferase ratio (AST/ALT ratio), AST-to-platelet ratio index (APRI), and body mass index, AST/ALT ratio, and diabetes (BARD) score by age groups”. NFS and FIB-4 were found to best predict advanced fibrosis with areas under curve of 0.71-0.76 and 0.62-0.80 respectively. However, the authors concluded that “While NFS and FIB-4 scores exhibit good diagnostic accuracy, FIB-4 is optimal in identifying NAFLD advanced fibrosis in the VHA. Easily implemented as a point-of-care clinical test, FIB-4 can be useful in directing patients that are most likely to have advanced fibrosis to GI/hepatology consultation and follow-up (Patel et al., 2018).”

Kim et al (2017) evaluated the “association between plasma miR-122 [microRNA-122] and treatment outcomes following transarterial chemoembolization (TACE) in hepatocellular carcinoma patients”. 177 patients were included, and miR-122 levels were measured. 112 patients exhibited TACE refractoriness.  Multivariate analyses showed that tumor number (hazard ratio [HR], 2.51) and tumor size (HR, 2.65) can independently predict overall TACE refractoriness. High miR-122 expression (> 100) was associated with early TACE refractoriness (within 1 year; HR, 2.77; 95% CI,) together with tumor number (HR, 22.73) and tumor size (HR, 4.90). Univariate analyses showed that high miR-122 expression tends to be associated with poor liver transplantation-free survival (HR, 1.42). However, this was statistically insignificant in multivariate analysis. The authors concluded that “High expression levels of plasma miR‐122 are associated with early TACE refractoriness in HCC patients treated with TACE (Kim et al., 2017).”

Suehiro et al (2018) performed a study analyzing “the importance of serum exosomal miRNA [microRNA] expression levels in HCC patients that underwent transarterial chemoembolization (TACE)”. 75 patients underwent TACE. Exosomal miR-122 expression levels significantly decreased after TACE. The expression levels of exosomal miR-122 before TACE were shown to correlate significantly with aspartate aminotransferase (r=0.31) and alanine aminotransferase (r=0.33) levels. According to the median relative expression of miR-122 after TACE/before TACE (miR-122 ratio) in liver cirrhosis patients (n=57), the patients with a higher miR-122 ratio had significantly longer disease-specific survival compared with that of the patients with the lower miR-122 ratio. A lower exosomal miR-122 ratio (HR 2.720) was associated with the disease-specific survival. The authors concluded that “the exosomal miR‑122 level alterations may represent a predictive biomarker in HCC patients with liver cirrhosis treated with TACE (Suehiro et al., 2018).”

Kar et al analyzed the performance of biomarkers implicated in hepatic inflammation. The authors enrolled 52 patients with NAFLD/NASH and evaluated the following biomarkers: IL-6, CRP, TNFα, MCP-1, MIP-1β, eotaxin, and VCAM-1. Serum IL-6 was found to have increased in patients with advanced fibrosis (2.71 pg/mL in fibrosis stages 3 and 4 compared to 1.26 pg/mL in stages 1-2 and 1.39 pg/mL in stage 0), but there were no other significant differences in CRP, TNFα, MCP-1, MIP-1β. VCAM-1 was noted to have increased by 55% over the mild fibrosis group and 40% over the no fibrosis group. VCAM-1 was also observed to have an area under curve of 0.87. The authors suggested that “addition of biomarkers such as IL-6 and VCAM-1 to panels may yield increased sensitivity and specificity for staging of NASH (Kar, Paglialunga, Jaycox, Islam, & Paredes, 2019).”

Srivastava et al performed a cost-benefit analysis of non-invasive fibrosis tests (NILTS) for non-alcoholic fatty liver disease (NAFLD). The authors compared the current standard of care, FIB-4, and the Enhanced Liver Fibrosis (ELF) panel. The simulations consisted of 10000 NAFLD patients. Standard care (SC) was compared to the following four scenarios: “FIB-4 for all patients followed by ELF test for patients with indeterminate FIB-4 results; FIB-4 followed by fibroscan for indeterminate FIB-4; ELF alone; and fibroscan alone”. The authors identified the following observations: “Introduction of NILT increased detection of advanced fibrosis over 1 year by 114, 118, 129 and 137% compared to SC in scenarios 2, 3, 4 and 5 respectively with reduction in unnecessary referrals by 85, 78, 71 and 42% respectively. Total budget spend [sic] was reduced by 25.2, 22.7, 15.1 and 4.0% in Scenarios 2, 3, 4 and 5 compared to £670 K at baseline.” The authors suggested that “use of NILT in primary care can increases early detection of advanced liver fibrosis and reduce unnecessary referral of patients with mild disease and is cost efficient (Srivastava et al., 2019).”

Weis et al evaluated miRNA expression’s ability to distinguish between hepatocellular carcinoma (HCC) and cirrhosis. 60 patients with chronic hepatitis C (CHC) were divided into three groups; 20 with fibrosis stages 0-2, 20 with cirrhosis, and 20 with cirrhosis and HCC. 372 miRNA sequences were measured. The authors found that a theoretical panel consisting of miRNA-122-5p, miRNA-486-5p, and miRNA-142-3p distinguished HCC from cirrhosis (area under the curve [AUC]= 0.94; sensitivity = 80%, specificity = 95%) outperforming AFP (AUC = 0.64). Another theoretical panel of miRNA-122-5p and miRNA-409-3p distinguished cirrhosis from mild disease (AUC = 0.80; sensitivity = 85%, specificity = 70%). The authors concluded that “MicroRNAs have great potential as diagnostic biomarkers in CHC, particularly in HCC where they outperform the only currently-used biomarker, AFP” (Weis et al., 2019).

Both Parikh et al and Kaswala et al performed studies evaluating the diagnostic accuracy of non-invasive markers for liver conditions. Parikh et al focused on chronic HBV infections while Kaswala et al studied nonalcoholic fatty liver. Tables detailing their summarized findings are listed below:

Diagnostic accuracy of most commonly used non-invasive fibrosis (≥F2) tests in chronic HBV infection from (Parikh et al., 2017)

Test

Cut-off

AUROC

Sensitivity (%)

Specificity (%)

Indirect markers

   FIB-4 index (high     cut-off)

3.25

N/A

16.2

73.6

   FIB-4 index (low cut-off)

1.45–1.62

0.78

65

77

   APRI (low cut-off)

0.5

0.79

84

41

   APRI (high cut-off)

1.5

 

49

84

   Forns index (low cut-off)

3.11

0.68

91.4

31.5

   Forns index (high cut-off)

5.11

N/A

42.5

75

 

 

 

 

 

Direct markers

       

   Hyaluronic acid

113–203

0.73

63–80

78–94

   Hepascore

0.32

0.75

74

69

   Fibrotest

0.38

0.77

65

78

   Fibrometer

0.47

0.84

73

80

   ELF

8.75

0.8

NA

NA

 

Diagnostic accuracy of most commonly used non-invasive fibrosis tests in nonalcoholic fatty liver (NAFL) from (Kaswala, Lai, & Afdhal, 2016)

Test

Cut-off

AUROC

Sensitivity (%)

Specificity (%)

AST/ALT ratio

1

0.83

21

90

AST to platelet ratio index (low cutoff)

0.45

0.67–0.94

30

93

AST to platelet ratio index (high cutoff)

1.5

     

BAAT score

2

0.84

71

80

BARD

2

0.8

86.8

32.5

ELF test

8.5–11.35

0.82–0.90

80

90

FibroMeter (low cutoff)

F3: 0.61

0.90–0.94

81

84

FibroMeter (high cutoff)

0.71

     

FibroTest (low cutoff)

0.3

0.81–0.92

15–77

77–90

FibroTest (high cutoff)

0.7

     

FIB-4 (low cutoff)

1.3–1.92

0.88

26–74

71–98

FIB-4 (high cutoff)

3.25

     

Hepascore

0.37

0.81

75.5

84.1

 

0.7

0.9

87

89

NAFLD (low cutoff)

−1.45

0.81

51

96

NAFLD (high cutoff)

0.67

     

AST- aspartate aminotransferase; APRI- AST to platelet ratio; BAAT- body mass index (BMI), age, alanine aminotransferase (ALT), triglycerides; BARD- BMI, AST/ALT ratio, diabetes; ELF- Enhanced Liver Fibrosis panel; FIB-4- Fibrosis-4 index; NAFLD – Nonalcoholic fatty liver disease

American Association for the Study of Liver Diseases (AASLD)
The 2015 AASLD and Infectious Diseases Society of America (IDSA) recommendations for testing, managing, and treating adults infected with hepatitis C virus stated that “Recently, noninvasive tests to stage the degree of fibrosis in patients with chronic HCV infection include models incorporating indirect serum biomarkers (routine tests such as aspartate transaminase, alanine transaminase [ALT], and platelet count), direct serum biomarkers (components of the extracellular matrix produced by activated hepatic stellate cells), and vibration‐controlled transient liver elastography. No single method is recognized to have high accuracy alone, and the results of each test must be interpreted carefully”. The guidelines further stated that “although liver biopsy is the diagnostic standard, sampling error and observer variability limit test performance, particularly when inadequate sampling occurs.  In addition, the test is invasive and minor complications are common, limiting patient and practitioner acceptance. Serious complications such as bleeding, although rare, are well recognized  (AASLD-IDSA, 2015).”

The 2018 AASLD and Infectious Diseases Society of America (IDSA) recommendations for HCV testing stated that “evaluation for advanced fibrosis using liver biopsy, imaging, and/or noninvasive markers is recommended for all persons with HCV infection, to facilitate an appropriate decision regarding HCV treatment strategy and to determine the need for initiating additional measures for the management of cirrhosis (eg, hepatocellular carcinoma screening). Rating: Class I, Level A” (AASLD-IDSA, 2018).

The 2018 AASLD update (Terrault et al., 2018) on prevention, diagnosis and treatment of chronic hepatitis B state that:

For Monitoring Patients with Chronic HBV Infection who are not currently on treatment “Alternative methods to assess fibrosis are elastography (preferred) and liver fibrosis biomarkers (e.g., FIB‐4 or FibroTest). If these noninvasive tests indicate significant fibrosis (≥F2), treatment is recommended.”

The 2018 AASLD practice guidelines (Chalasani et al., 2017) on the diagnosis and management of nonalcoholic fatty liver disease recommend:

  • “In patients with NAFLD, metabolic syndrome predicts the presence of steatohepatitis, and its presence can be used to target patients for a liver biopsy.”
  • “NFS or FIB-4 index are clinically useful tools for identifying NAFLD patients with higher likelihood of having bridging fibrosis (stage 3) or cirrhosis (stage 4).”
  • “Vibration controlled transient elastography or magnetic resonance elastography are clinically useful tools for identifying advanced fibrosis in patients with NAFLD. “

The AASLD does not mention miRNA for assessment in liver disease. 

American Gastroenterological Association (AGA)
The 2017 guidelines (Lim, Flamm, Singh, & Falck-Ytter, 2017) on the Role of Elastography in the Evaluation of Liver Fibrosis state that:

  • “In patients with chronic hepatitis C, the AGA recommends vibration controlled transient elastography, if available, rather than other nonproprietary, noninvasive serum tests (APRI, FIB-4) to detect cirrhosis.”
  • “In patients with chronic hepatitis B, the AGA suggests vibration controlled transient elastography (VCTE) rather than other nonproprietary noninvasive serum tests (ie, APRI and FIB-4) to detect cirrhosis.”
  • “The AGA makes no recommendation regarding the role of VCTE in the diagnosis of cirrhosis in adults with NAFLD.”

World Health Organization (WHO)
In March 2015, the WHO released Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. In the section titled “Non-invasive Assessment of Liver Disease Stage at Baseline and during Follow up”, the following is noted: aspartate aminotransferase (AST)-to-platelet ratio index (APRI) is recommended as the preferred non-invasive test (NIT) to assess for the presence of cirrhosis (APRI score >2 in adults) in resource-limited settings. Transient elastography (e.g., FibroScan) or FibroTest may be the preferred NITs in settings where they are available and cost is not a major constraint (WHO, 2015).

The WHO also published guidelines for management of patients with Hepatitis C. In it, they suggest “that aminotransferase/platelet ratio index (APRI) or FIB-4 be used for the assessment of hepatic fibrosis rather than other non-invasive tests that require more resources such as elastography or FibroTest”. However, they do note that “FibroScan, which is more accurate than APRI and FIB-4, may be preferable in settings where the equipment is available and the cost of the test is not a barrier to testing.”

The WHO does not mention miRNA as a tool for assessment of hepatitis (WHO, 2018).

US Preventive Services Task Force (USPSTF)
The USPSTF published their final recommendation statement on Hepatitis C screening in 2013 (current as of August 2019). Regarding non-invasive tests, it stated that “the USPSTF found more than 100 studies (including 8 of good quality) that compared various noninvasive laboratory-based diagnostic tests with liver biopsy as the reference standard. Sensitivity and specificity varied depending on the cutoff used to define a positive test result. Several of the blood indices were associated with an area under the receiver-operating characteristic curve of 0.75 to 0.86 for fibrosis and 0.80 to 0.91 for cirrhosis (considered good to very good values for diagnostic accuracy).” The USPSTF remarked that “various noninvasive tests with good diagnostic accuracy are possible alternatives to liver biopsy for diagnosing fibrosis or cirrhosis”(USPSTF, 2013).

National Institute for Health and Care Excellence (NICE)
NICE has released guidelines regarding chronic liver conditions. They note that the enhanced liver fibrosis test (ELF) may be considered in patients with NAFLD to test for advanced liver fibrosis (NICE, 2016).

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity
These joint guidelines include recommendations for fibrosis, mentioning ELF, FibroTest, NFS, and FIB-4.  Their recommendations include the following:

  • “Biomarkers and scores of fibrosis, as well as transient elastography, are acceptable non-invasive procedures for the identification of cases at low risk of advanced fibrosis/cirrhosis (A2). The combination of biomarkers/ scores and transient elastography might confer additional diagnostic accuracy and might save a number of diagnostic liver biopsies (B2).”
  • “Monitoring of fibrosis progression in clinical practice may rely on a combination of biomarkers/scores and transient elastography, although this strategy requires validation (C2).”
  • “The identification of advanced fibrosis or cirrhosis by serum biomarkers/scores and/or elastography is less accurate and needs to be confirmed by liver biopsy, according to the clinical context (B2).”
  • The guidelines observe that due to non-invasive tests’ high negative predictive values, they “may be confidently used for first-line risk stratification to exclude severe disease.” Still, they state that “There is no consensus on thresholds or strategies for use in clinical practice when trying to avoid liver biopsy. Some data suggest that the combination of elastography and serum markers performs better than either method alone. Importantly, longitudinal data correlating changes in histological severity and in non-invasive measurements are urgently needed.”
  • For non-alcoholic steatohepatitis (NASH), the guidelines state that “to date, non-invasive tests are not validated for the diagnosis of NASH” and addresses CK-18 as a proposed biomarker.
  • For monitoring of NAFLD, the guidelines state that “Monitoring should include routine biochemistry, assessment of comorbidities and non-invasive monitoring of fibrosis” (EASL, 2016).

The EASL also released guidelines on management of Hepatitis C. In it, they recommend that “Fibrosis stage must be assessed by non-invasive methods initially, with liver biopsy reserved for cases where there is uncertainty or potential additional aetiologies”. Non-invasive methods include FibroScan, ARFI, Aixplorer, FibroTest, APRI, and FIB-4 (EASL, 2018).

Guidelines for Hepatitis B were also published. In it, EASL remarks that “the diagnostic accuracy of all non-invasive methods is better at excluding than confirming advanced fibrosis or cirrhosis”. Non-invasive methods include assessment of serum biomarkers of liver fibrosis (EASL, 2017).

The EASL also published guidelines titled “Non-invasive tests for evaluation of liver disease severity and prognosis”. In it, they state the following:

  • “Serum biomarkers can be used in clinical practice due to their high applicability (>95%) and good interlaboratory reproducibility. However, they should be preferably obtained in fasting patients (particularly those including hyaluronic acid) and following the manufacturer’s recommendations for the patented tests”.
  • “Serum biomarkers of fibrosis are well validated in patients with chronic viral hepatitis (with more evidence for HCV than for HBV and HIV/HCV coinfection). They are less well validated in NAFLD and not validated in other chronic liver diseases.”
  • “Their performances are better for detecting cirrhosis than significant fibrosis.”
  • “FibroTest®, APRI and NAFLD fibrosis score are the most widely used and validated patented and nonpatented tests.”
  • “Among the different available strategies, algorithms combining TE and serum biomarkers appear to be the most attractive and validated one”
  • “HCV patients who were diagnosed with cirrhosis based on non-invasive diagnosis should undergo screening for HCC and PH and do not need confirmatory liver biopsy.”
  • “Non-invasive assessment including serum biomarkers or TE can be used as first line procedure for the identification of patients at low risk of severe fibrosis/ cirrhosis.”
  • “The identification of significant fibrosis is less accurate with non-invasive tests as compared to liver biopsy and may necessitate, according to the clinical context, histological confirmation.”
  • “Follow-up assessment by either serum biomarkers or TE for progression of liver fibrosis should be performed among NAFLD patients at a 3 year interval (EASL, 2015).” 

NONINVASIVE IMAGING
Validation of the clinical use of any diagnostic test focuses on 3 main principles: (1) technical reliability of the test; (2) clinical validity of the test (e.g., sensitivity, specificity, and PPV and NPV in relevant populations of patients and compared with the criterion standard); and (3) effect on patient outcomes of the test (i.e., how the results of the diagnostic test will be used to improve management of the patient).

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

Transient Elastography (FibroScan) 

Clinical Context and Test Purpose
The question addressed in this portion of the evidence review is: Does use of transient elastography for detecting liver fibrosis lead to an improvement in health outcomes in patients with chronic liver disease?

The following PICOTS were used to select literature to inform this review. 

Patients
The relevant population of interest is patients with chronic liver disease. 

Interventions
The intervention of interest is transient electrography. 

Comparators
The comparator of interest is liver biopsy, other noninvasive radiologic tests, or multianalyte serum assays. 

Outcomes
The outcomes of interest are test accuracy, test validity, morbid events, and treatment-related morbidity. 

Timing
The timing of testing is when patients have been diagnosed with chronic liver disease and there is a need to know the degree of liver fibrosis. 

Setting
The testing would be performed in the specialty setting. 

Technical Reliability
Fraquelli et al (2007) cited high intra- and interobserver agreement for transient elastography results of 96% to 98% and 89% to 98%, respectively.45 In a retrospective study of 38,464 Chinese patients with HBV, HCV, liver cirrhosis, ALD, autoimmune liver disease, and hepatocellular carcinoma, Ji et al (2014) examined clinical and biologic factors associated with transient elastography reliability.46 Trained operators performed 10 transient elastography measurements per patient in the target area. Results deemed “unsuccessful” were those that obtained no values after at least 10 shots. Results deemed “unreliable” were those for which the interquartile range divided by the median was greater than 0.30 or if the median was greater than 7.1 kilopascals (kPa). Approximately 2.5% of examinations were unsuccessful and 0.85% were unreliable. Success and reliability were independently associated with BMI, female sex, age, and size of intercostal spaces. Castera et al (2010) estimated that no valid shots could be obtained in 3% of examinations while 15% of examinations produced unreliable results in a study of 13,369 examinations over a 5-year period.47 Success and reliability were associated with BMI, operator experience, age, female sex, hypertension, type 2 diabetes, and waist circumference.

Clinical Validity
There is extensive literature on the use of transient elastography to gauge liver fibrosis and cirrhosis. Summaries of systematic reviews are shown in Tables 2 and 3. Brener et al (2015) performed a health technology assessment summarizing many of the systematic reviews below.48 The assessment focused on reviews of the diagnostic accuracy and effect on patient outcomes of transient elastography for liver fibrosis in patients with HCV, HBV, NAFLD, ALD, or cholestatic diseases. Fourteen systematic reviews of transient elastography with biopsy reference standard shown below were included in the Brener health technology assessment, summarizing more than 150 primary studies.49-62 There was variation in the underlying cause of liver disease and the cutoff values of transient elastography stiffness used to define Metavir stages in the systematic reviews. There did not appear to be a substantial difference in diagnostic accuracy for one disease over any other. The reviews demonstrated that transient elastography has good diagnostic accuracy compared with biopsy for the assessment of liver fibrosis and steatosis.

Crossan et al (2015) found that Fibroscan was the noninvasive liver test most assessed in validation studies across liver diseases (37 studies in HCV, 13 in HBV, 8 in NAFLD, 6 in ALD).5 Cutoffs for positivity for fibrosis staging varied between diseases and were frequently not prespecified or validated: HCV, 5.2 to 10.1 kPa in the 37 studies for Metavir stages ≥ F2; HBV, 6.3 to 8.9 kPa in 13 studies for stages ≥ F2; NAFLD, 7.5 to 10.4 kPa in 8 studies for stages ≥ F3; ALD, 11.0 to 12.5 in 4 studies for stages ≥ F3. Summary sensitivities and specificities by disease are shown in Table 2. The overall sensitivity and specificity for cirrhosis including all diseases (65 studies; cutoffs range, 9.2-26.5 kPa) were 89% (95% CI, 86% to 91%) and 89% (95 % CI, 87% to 91%), respectively. The rate of uninterpretable results, when reported, with FibroScan (due to <10 valid measurements; success rate, <60%; interquartile range, >30%) was 8.5% in HCV, and 9.6% in NAFLD. 

Table 2. Transient Elastography Systematic Review Characteristics 

Study (Year)

Dates

Studies

N

Population

Bota et al. (2013)50

Up to May 2012

13

1,163

Chronic hepatitis

Chon et al. (2012)51

2002 to Mar 2011

18

2,772

HBV

Crossan et al. (2015)6

1998 to April 2012

66

NR

HCV, HBV, NAFLD, ALD

Friedrich-Rust et al. (2008)53

2002 to Apr 2007

50

11,275

All causes of liver disease

Friedrick-Rust et al. (2012)52

Up to Oct 2010

8

518

All causes of liver disease

Geng et al. (2016)64

Up to Jan 2015

57

10,569

Multiple causes of liver disease

Kwok et al. (2014)54

Up to Jun 2013

22

1,047

NAFLD

Li et al. (2016)65

Jan 2003 to Nov 2014

27

4,386

HBV

Pavlov et al. (2015)66

Up to Aug 2014

14

834

ALD

Poynard et al. (2008)55

1991 to 2008

66

NR

All causes of liver disease

Poynard et al. (2011)56

Feb 2001 to Dec 2010

18

2,714

HBV

Shaheen et al. (2007)57

Jan 1997 to Oct 2006

12

1,981

HCV

Shi et al. (2014)58

Up to May 2013

9

1,771

All causes of steatosis

Steadman et al. (2013)59

2001 to Jun 2011

64

6,028

HCV, HBV, NAFLD, chronic liver disease, liver transplant

Stebbing et al. (2010)60

NR, prior to Feb 2009

22

4,625

All causes of liver disease

Talwalkar et al. (2007)61

 

 2,083

All causes of liver disease 

Tsochatzis et al. (2011)62

Up to May 2009

40

7,661

All causes of liver disease

Tsochatzis et al. (2014)63

1998 to Apr 2012

302

NR

HCV, HBV, ALD, NAFLD

Xu et al. (2015)67

Up to Dec 2013

19

3,113

HBV

ALD: alcoholic liver disease; HBV: hepatitis B virus; HCV: hepatitis C virus; NAFLD: nonalcoholic fatty liver disease; NR: not reported. 

Table 3. Transient Elastography Systematic Reviews Diagnostic Accuracy Results

Study     Significant Fibrosis (i.e., Metavir Stage F2-F4) Cirrhosis (i.e., Metavir Stage F4)   
  Population Studies/Sample Size

AUROC (95% CI)
Sensitivigy (95 CI)
Specificity (95% CI)

Studies/s Sample Size

AUROC (95% CI)
Sensitivity (95%  CI)
Specificity (95% CI)

 Bota et al. (2013) Multiple diseases 10/1,016

0.87 (0.83 to 0.89)
78% (72% to 83%)
84% (75% to 90%) 

13/1,163 

0.93 (0.91 to 0.95)
89% (80% to 94%)
87% (82% to 91%) 

  HCV       4/NR 

NR
92% (78% to 97%)
86% (82% to 90%) 

 Chon et al. (2012)  Chronic HBV  12/2,000

0.86 (0.86 to 0.86)
74.3% (NR)
78.3% (NR) 

16/2,614  

0.93 (0.93 to 0.93)
84.6% (NR)
81.5% (NR) 

 Crossan et al. (2015)  HCV  37/NR

NR
79% (74% to 84%)
83% (77% to 88%) 

36/NR  

NR
89% (84% to 92%)
91% (89% to 93%) 

   HBV 13/NR  

NR
71% (62% to 78%)
84% (74% to 91%) 

19/NR  

NR
86% (79% to 91%)
85% (78% to 89%) 

  NAFLD       4/NR    NR
96% (83% to 99%)
89% (85% to 92%)
  ALD  1/NR 

NR
81% (70% to 88%)
92% (76% to 98%) 

4/NR 

NR
87% (64% to 96%)
82% (67% to 91%) 

Friedrich-Rust (2008)  Multiple diseases   25/3,685 

0.84 (0.82 to 0.86)
NR
NR 

25/4,557 

0.94 (0.93 to 0.95)
NR
NR 

  HCV  NR 

0.84 (0.80 to 0.86)
NR
NR 

   
Friedrick-Rust et al. (2012)   No summary statistics reported for transient elastography     
Geng et al. (2016)  Multiple diseases      57/10,569 

0.93 (NR)
81% (79% to 83%)
88% (87% to 89%) 

Kwok et al. (2014)  NAFLD   7/800

0.83 (0.79 to 0.87)
0.79 (0.72 to 0.84)
0.75 (0.71 to 0.79) 

6/639 

0.96 (0.94 to 0.99)
92% (82% to 97%)
92% (86% to 98%) 

Li et al. (2016)  HBV   19/NR  

0.88 (0.85 to 0.91)
81% (76% to 85%)
82% (71% to 87%) 

24/NR 

0.93 (0.91 to 0.95)
86% (82% to 90%)
88% (84% to 90%) 

Pavlov et al. (2015)  ALD   7/338 

NR
94% (86% to 97%)
89% (76% to 95%) 

7/330 

NR
95% (87% to 98%)
71% (56% to 82%) 

Poynard et al. (2008)  No summary statistics reported for transient elastography     
Poynard et al. (2011)  HBV   4/NR  

0.84 (0.78 to 0.89)
NR 
NR

NR 

0.93 (0.87 to 0.99)
NR 
NR

Shaheen et al. (2007)  HCV   4/NR  

0.84 (0.78 to 0.89)
NR
NR 

NR   0.93 (0.87 to 0.99)
NR
NR 
Shi et al. (2014)  No summary statistics reported. Concluded that transient elastography controlled attenuation parameter has good sensitivity and specificity for diagnosing steatosis, but it has limited utility      
Steadman et al. (2013)  Multiple diseases  45/NR 

0.88 (0.84 to 0.90)
80% (76% to 83%)
81% (77% to 85%) 

49/NR 

0.94 (0.91 to 0.96)
86% (82% to 89%)
89% (87% to 91%) 

  HBV   5/710

0.81 (0.78 to 0.84)
77% (68% to 84%)
72% (55% to 85%) 

8/1,092 

0.86 (0.82 to 0.89)
67% (57% to 75%)
87% (83% to 91%) 

  HCV   13/2,732

0.89 (0.86 to 0.91)
76% (61% to 86%)
86% (77% to 92%) 

12/2,887 

0.94 (0.92 to 0.96)
85% (77% to 91%)
91% (87% to 93%) 

  NAFLD   5/630

0.78 (0.74 to 0.82)
77% (70% to 83%)
75% (70% to 79%) 

4/469  

0.96 (0.94 to 0.97)
92% (77% to 98%)
95% (88% to 98%) 

Stebbing et al. (2010)   Multiple diseases  17/3,066  

NR
72% (71% to 72%)
82% (82% to 83%) 

17/405 

NR
84% (84% to 85%)
95% (94% to 95%) 

Talwalkar et al. (2007)  Multiple diseases   7/>1,100 

0.87 (0.83 to 0.91)
70% (67% to 73%)
84% (80% to 88%) 

9/2,083  

0.96 (0.94 to 0.98)
87% (84% to 90%)
91% (89% to 92%) 

Tsochatzis et al. (2011)  Multiple diseases   31/5,919 

NR
79% (74% to 82%) 
78% (72% to 83%)

30/6,530 

NR
83% (79% to 86%)
89% (87% to 91%) 

  HCV 14/NR  

NR
78% (71% to 84%)
80% (71% to 86%) 

11/NR  

NR
83% (77% to 88%)
90% (87% to 93%) 

  HBV   4/NR 

NR
84% (67% to 93%)
78% (68% to 85%) 

6/NR  

NR
80% (61% to 91%)
86% (82% to 94%) 

Tsochatzis et al. (2014)   HCV   37/NR  

0.87 (0.83 to 0.90)
79% (74% to 84%)
83% (77% to 88%) 

36/NR 

0.96 (0.94 to 0.97)
89% (84% to 92%)
91% (89% to 93%) 

  HBV   13/NR  

0.83 (0.76 to 0.90)
71% (62% to 78%)
84% (74% to 91%) 

13/NR  

0.92 (0.89 to 0.96)
86% (79% to 91%)
85% (78% to 89%) 

  NAFLD       4/NR  

0.96 (0.94 to 0.99)
96% (83% to 99%)
89% (85% to 92%) 

  ALD       6/NR  

0.90 (0.87 to 0.94)
86% (76% to 92%)
83% (74% to 89%) 

Xu et al. (2015)  HBV   14/2,318 

0.82 (0.78 to 0.86)
NR
NR 

18/2,996 

0.91 (0.89 to 0.93)
NR
NR 

ALD: alcoholic liver disease; AUROC: area under the ROC: receiver operating characteristic curve; CI: confidence interval; HBV: hepatitis B virus; HCV: hepatitis C virus; NAFLD: nonalcoholic fatty liver disease; NR: not reported.  

Clinical Utility
There are currently no published studies that directly demonstrate the effect on patient outcomes of FibroScan. FibroScan is used extensively in practice to make management decisions. In addition, FibroScan was allowed as an alternative to biopsy for to diagnose fibrosis or cirrhosis to establish trial eligibility in several trials (ION-1,-3; VALENCE; ASTRAL-2, -3, -4) that confirmed efficacy of HCV treatments.16-21 For example, in the VALENCE trial, cirrhosis could be defined by liver biopsy, FibroTest, or Fibroscan showing cirrhosis or results 12.5 kPa or greater. In VALENCE, FibroScan was used to determine cirrhosis in 74% of the participants. 

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

OTHER NONINVASIVE IMAGING  

Clinical Context and Test Purpose
The question addressed in this portion of the evidence review is: Does use of noninvasive imaging other than transient elastography for detecting liver fibrosis lead to an improvement in health outcomes in patients with chronic liver disease? 

The following PICOTS were used to select literature to inform this review.  

Patients
The relevant population of interest is patients with chronic liver disease.  

Interventions
The intervention of interest is noninvasive imaging other than transient elastography.  

Comparators
The comparator of interest is liver biopsy, other noninvasive radiologic tests, or multianalyte serum assays.  

Outcomes
The outcomes of interest are test accuracy, test validity, morbid events, and treatment-related morbidity.  

Timing
The timing of testing is when patients have been diagnosed with chronic liver disease and there is a need to know the degree of liver fibrosis.  

Setting
The testing would be performed in the specialty setting. 

Acoustic Radiation Force Impulse Imaging  

Technical Reliability
Piscaglia et al (2011) demonstrated that the interoperator reproducibility of ARFI was high (r=0.874) in a study of 133 patients with chronic liver disease, and the method was feasible for all patients enrolled.68 Other measures of technical reliability were not found.  

Clinical Validity
The systematic reviews in Tables 4 and 5 have reported on diagnostic accuracy of ARFI.

Table 4. Acoustic Radiation Force Impulse Imaging Systematic Review Characteristics  

Study (Year)

Dates

Studies

N

Population

Nierhoff et al (2013)69

2007 to Feb 2012

36

3,951

Multiple diseases

Bota et al (2013)49

Up to May 2012

6

518

Chronic hepatitis

Crossan et al (2015)6

1998 to Apr 2012

4

Not reported

Hepatitis C virus

Guo et al (2015)70

Up to Jun 2013

15

2,128

Multiple diseases

Liu et al (2015)71

Up to Jul 2014

7

723

Nonalcoholic fatty liver disease

Hu et al (2017)72 

Up to Apr 2016 

15 

2,691 

Chronic hepatitis B or C

  Table 5. Acoustic Radiation Force Impulse Imaging Systematic Reviews of Diagnostic Accuracy     

Study

 

Significant Fibrosis (i.e., Metavir Stages F2-F4)

Cirrhosis (i.e., Metavir Stage F4)

 

Population

Studies/Sample Size   

AUROC (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) 

Studies/Sample Size     

AUROC (95% CI)
Sensitivity (95% CI)
Specificity (95% CI) 

Nierhoff et al (2013))69

Multiple diseases

26/NR

0.83 (0.80 to 0.86)
NR
NR

27/NR

0.91 (0.89 to 0.93)
NR
NR

Bota et al (2013))49

 

Chronic hepatitis

6/518

 

0.88 (0.83 to 0.93)
NR
NR

 

0.92 (0.87 to 0.98)
NR
NR

Crossan et al (2015))50

HCV 

4/NR 

NR
85% (69% to 94%)
89% (72% to 97%) 

 

 

Guo et al (2015)70

Multiple diseases

 13/NR

NR
76% (73% to 78%)
80% (77% to 83%)

14/NR

NR
88% (84% to 91%)
80% (81% to 84%)

Liu et al (2016)71

NAFLD

7/723 

NR
80% (76% to 84%)
85% (81% to 89%)

 

 

Hu et al (2017)72 

HBV, HCV 

15/NR 

88% (85% to 91%)
75% (69% to 78%)
85% (81% to 89%) 

 

 

AUROC: area under the receiver operating characteristic curve; CI: confidence interval; HCV: hepatitis C virus; NAFLD: nonalcoholic fatty liver disease; NR: not reported.   

Clinical Utility 
There are currently no published studies that directly demonstrate effect on patient outcomes of ARFI.  

Subsection Summary: Acoustic Radiation Force Impulse Imaging 
The use of ARFI has been evaluated in viral hepatitis and NAFLD. Moreover, many have noted that ARFI has potential advantages over FibroScan; it can be implemented on a standard ultrasound machine, may be more applicable for assessing complications such as ascites and may be more applicable in obese patients. ARFI appears to have similar diagnostic accuracy to FibroScan, but there are fewer data available on performance characteristics. Validation studies have used varying cutoffs for positivity.  

Magnetic Resonance Elastography  

Technical Reliability 
A 2014 phase 1 study examined the interobserver agreement between 2 pathologists who assessed with MRE using biopsy results from 103 patients with chronic hepatitis B and C.73 The intraclass correlation coefficient (ICC) was very high at 0.99 (95% CI, 0.98 to 1.00). For the same patients, the ICC for these 2 pathologists using Metavir was 0.91 (95% CI, 0.86 to 0.94; difference with 23 MRE, p<0.001). In a second phase 1 study of 110 patients and 10 normative volunteers, the ICC for 2 raters was 0.993 for MRE. The absolute differences in elasticity assigned by the 2 raters were less than 0.8 kPa for more than 95% of the subjects.74 Twenty-one patients had also undergone liver biopsy. Shi et al (2014) demonstrated that, in 22 healthy volunteers liver, MRE had good short and mid-term (within 6 mo) repeatability.75 Venkatesh et al (2014) showed that liver stiffness measurements on MRE performed 4 to 6 weeks apart in a study of 41 healthy Asian volunteers had an ICC of 0.9 (95% CI, 0.78 to 0.96) and a within-subject coefficient of variation of 2.2% to 11.4%.76 Yin et al (2016) retrospectively analyzed 1,377 consecutive MRE examinations performed between 2007 and 2010 for patients with various chronic liver diseases.77 MRE had a success rate of 94% and highly reproducible measurements (r=0.972, p<0.001). BMI was not associated with success. 

Clinical Validity
The systematic reviews in Tables 6 and 7 summarize the diagnostic accuracy of MRE. MRE has been studied primarily in hepatitis and NAFLD. 

Table 6. Magnetic Resonance Elastography Systematic Review Characteristics

Study (Year)

Dates

Studies

N

Population

Crossan et al. (2015)5

1998 to Apr 2012

3

Not reported

Chronic liver disease

Guo et al. (2015)70

Up to Jun 2013

11

982

Multiple diseases

Singh et al. (2015)78

2003 to Sep 2013

12

697

Chronic liver disease

Singh et al. (2016)79

Up to Oct 2014

9

232

Nonalcoholic fatty liver disease

 Table 7. Magnetic Resonance Elastography Systematic Reviews of Diagnostic Accuracy

Study   Significant Fibrosis (i.e., Stage F2-F4) Cirrhosis (i.e., Stage F4)
  Population Studies/Sample Size

AUROC (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)

Studies/Sample Size

AUROC (95% CI)
Sensitivity (95% CI)
Specificity (95% CI)

Crossan et al. (2015)5 Chronic liver disease 3/NR

NR
94% (13% to 100%)
92% (72% to 98%)

   
Guo et al. (2015)70 Multiple diseases 9/NR

NR
87% (84% to 90%)
94% (91% to 97%)

 

NR
93% (88% to 96%)
91% (88% to 93%)

Singh et al. (2015)78 Chronic hepatitis 12/697

0.84 (0.76 to 0.92)
73% (NR)
79% (NR)

12/697

0.92 (0.90 to 0.94)
91% (NR)
81% (NR)

Singh et al. (2016)79 NAFLD 9/232

0.87 (0.82 to 0.93)
79% (76% to 90%)
81% (72% to 91%)

9/232

0.91 (0.76 to 0.95)
88% (82% to 100%)
87% (77% to 97%)

AUROC: area under the receiver operating characteristic curve; CI: confidence interval; NAFLD: nonalcoholic fatty liver disease; NR: not reported.  

Clinical Utility
There are currently no published studies that directly demonstrate the effect on patient outcomes of MRE. 

Subsection Summary: Magnetic Resonance Elastography
MRE has a high success rate and is highly reproducible across operators and time. The diagnostic accuracy also appears to be high. In particular, MRE has high diagnostic accuracy for detection of fibrosis in NAFLD, independent of BMI and degree of inflammation. However, further validation is needed to determine standard cutoffs and confirm performance characteristics because confidence intervals for estimates are wide. MRE is not widely available. 

Real-Time Tissue Elastography (HI VISION 15 Preirus

Technical Reliability
In a study of 70 hospitalized patients with HCV, RTE using the HI VISION 15 Preirus was performed at 4 liver locations by 2 independent observers. The elastic ratio (ratio of the value in the intrahepatic venous small vessels divided by the value in the hepatic parenchyma) was highly correlated between the 2 examiners (R2=0.869, p<.001) and consistent across liver locations (κ=0.835, ICC=0.966).80 Other measures of technical performance were not found. 

Clinical Validity
In 2014, Hong et al reported results of a meta-analysis RTE for staging fibrosis in multiple diseases.81 Thirteen studies (total N=1,347 patients) published between April 2000 and April 2014 that used liver biopsy or transient elastography as the reference standard were included. Different quantitative methods were used to measure liver stiffness: Liver Fibrosis Index (LFI), Elasticity Index, elastic ratio 1 (ER1), and elastic ratio 2 (ER2) in the included studies. For predicting significant fibrosis (stage ≥ F2), the pooled sensitivities for LFI and ER1 were 78% (95% CI, 70% to 84%) and 86% (95% CI, 80% to 90%), respectively. The specificities were 63% (95% CI, 46% to 78%) and 89% (95% CI, 83% to 94% and the AUROCs were 0.79 (95% CI, 0.75 to 0.82) and 0.94 (95% CI, 0.92 to 0.96), respectively. For predicting cirrhosis (stage F4), the pooled sensitivities of LFI, ER1, and ER2 were 79% (95% CI, 61% to 91%), 96% (95% CI, 87% to 99%), and 79% (95% CI, 61% to 91%), respectively. The specificities were 88% (95% CI, 81% to 93%) for LFI, 89% (95% CI, 83% to 93%) for ER1, and 88% (95% CI, 81% to 93%) for ER2, and the AUROCs were 0.85 (95% CI, 0.81 to 0.87), 0.93 (95% CI, 0.94 to 0.98), and 0.92 (95% CI NR), respectively. Pooled estimates for Elasticity Index were not performed due to insufficient data.

Kobayashi et al published results of a meta-analysis of RTE for staging liver fibrosis in 2015.82 They included 15 studies (total N=1,626 patients) published through December 2013, including patients with multiple liver diseases and healthy adults. A bivariate random-effects model was used to estimate summary sensitivity and specificity. The summary AUROC, sensitivity, and specificity were 0.69  (precision NR), 79% (95% CI, 75% to 83%), and 76% (95% CI, 68% to 82%), respectively, for detection of significant fibrosis (stage ≥ F2) and 0.72 (precision NR), 74% (95% CI, 63% to 82%), and 84% (95% CI, 79% to 88%) for detection of cirrhosis. Reviewers found evidence of heterogeneity due to differences in study populations, scoring methods, and cutoffs for positivity. They also found evidence of publication bias based on funnel plot asymmetry. 

Clinical Utility
There are currently no published studies that directly demonstrate the effect on patient outcomes of RTE. 

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

Section Summary: Noninvasive Radiological Methods Other Than Transient Elastography
The available studies suggest that other radiologic methods (AFRI, MRE, RTE) may have similar performance for detection of significant fibrosis or cirrhosis. However, the 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 and an indirect chain cannot be constructed due to the lack of sufficient evidence on clinical validity. 

SUMMARY OF EVIDENCE 
Multianalyte Serum Assays
For individuals who have chronic liver disease who receive FibroSURE serum panels, the evidence includes systematic reviews of more than 30 observational studies (>5,000 patients). Relevant outcomes are test accuracy and validity, morbid events, and treatment-related morbidity. FibroSURE has been studied in populations with viral hepatitis, nonalcoholic fatty liver disease, and alcoholic liver disease. 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 RCTs that showed the efficacy of hepatitis C virus 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 a meaningful improvement in the net health outcome.

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

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 accuracy and validity, morbid events, and treatment-related morbidity. Transient elastography (FibroScan) has been studied in populations with viral hepatitis, nonalcoholic fatty liver disease, and alcoholic liver disease. 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 RCTs showed the efficacy of hepatitis C virus 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 a meaningful improvement in the net health outcome.

For individuals who have chronic liver disease who receive noninvasive radiologic methods other than transient elastography for liver fibrosis measurement, the evidence includes systematic reviews of observational studies. Relevant outcomes are test accuracy and validity, morbid events, and treatment-related morbidity. Other radiologic methods (e.g., magnetic resonance elastography, real-time transient elastography, acoustic radiation force impulse imaging) may have similar performance for detecting significant fibrosis or cirrhosis. Studies have frequently included varying cutoffs not prespecified or validated. Given these limitations and the imperfect reference standard, it is difficult to interpret performance characteristics. There is no direct evidence that other noninvasive radiologic methods improve health outcomes; 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 the effects of the technology on health outcomes.

CLINICAL INPUT FROM PHYSICIAN SPECIALTY SOCIETIES AND ACADEMIC MEDICAL CENTERS
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 3 physician specialty societies and 3 academic medical centers while this review was under review in 2014. Most reviewers considered noninvasive techniques for the evaluation and monitoring of chronic liver disease to be investigational, both individually and in combination. 

PRACTICE GUIDELINES AND POSITION STATEMENTS 

Nonalcoholic Fatty Liver Disease 

American Gastroenterological Association et al
The 2012 practice guidelines on the diagnosis and management of nonalcoholic fatty liver disease (NAFLD), developed by the American Gastroenterological Association, the American Association for the Study of Liver Diseases, and the American College of Gastroenterology did not reference multianalyte assays with algorithmic analyses for liver fibrosis evaluation and management.83 The guidelines mentioned that while transient elastography has shown high sensitivity and specificity in identifying advanced fibrosis in patients with NAFLD, the test is not as accurate when used in patients with high body mass index. 

National Institute for Health and Care Excellence
In 2016, the National Institute for Health and Care Excellence (NICE) published guidance on the assessment and management of NAFLD.84 The guidance did not reference elastography or multianalyte assays with algorithmic analyses. The guidance recommended the enhanced liver fibrosis test to test for advanced liver fibrosis. 

American College of Gastroenterology
In 2017, the American College of Gastroenterology published guidelines on the role of elastography in chronic liver disease. The guidelines indicated that, in adults with NAFLD, vibration-controlled transient elastography (VCTE) has better diagnostic performance for diagnosing cirrhosis than the aspartate aminotransferase to platelet ratio index and Fibrosis-4 Index (FIB-4) (very low quality of evidence).85

Moreover, the guidelines stated that, in adults with NAFLD, magnetic resonance-guided elastography has little or no increased diagnostic accuracy for identifying cirrhosis compared with VCTE in patients who have cirrhosis, and has higher diagnostic accuracy than VCTE in patients who do not have cirrhosis (very low quality of evidence). 

Hepatitis B and C Viruses 

National Institute for Health and Care Excellence
In 2013, NICE published guidance on the management and treatment of patients with hepatitis B.86 The guidance recommended offering transient elastography as the initial test in adults diagnosed with chronic hepatitis B, to inform the antiviral treatment decision (see Table 8).

 Table 8. Antiviral Treatment Recommendations by Transient Elasticity Score

Transient Elasticity Score

Antiviral Treatment

>11 kPa

Offer antiviral treatment

6-10 kPa

Offer liver biopsy to confirm fibrosis level prior to offering antiviral treatment

<6 kPa plus abnormal (ALT)

Offer liver biopsy to confirm fibrosis level prior to offering antiviral treatment

<6 plus normal ALT

Do not offer antiviral treatment

ALT: alanine aminotransferase 

As of September 2016, NICE has placed a pause on the development of the guidance on hepatitis C, citing instability and costs in the availability of treatments for the condition. 

American Association for the Study of Liver Diseases and Infectious Diseases Society of America
The 2016 American Association for the Study of Liver Diseases and Infectious Diseases Society of America guidelines for testing, managing, and treating hepatitis C virus (HCV) recommended that, for counseling and pretreatment assessment purposes, the following should be completed:87 

“Evaluation for advanced fibrosis, using liver biopsy, imaging, or noninvasive markers, is recommended in all persons with HCV infection to facilitate an appropriate decision regarding HCV treatment strategy and determine the need for initiating additional measures for the management of cirrhosis (eg, hepatocellular carcinoma screening). 
Rating: Class I, Level A (evidence and/or general agreement; data derived from multiple randomized trials, or meta-analyses)” 

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

American College of Gastroenterology 
Guidelines published by the American College of Gastroenterology in 2017 on the role of elastography in chronic liver disease indicated that, in adults with chronic hepatitis B virus and HCV, VCTE has better diagnostic performance for diagnosing cirrhosis than the aminotransferase to platelet ratio index and FIB- 4 (moderate quality of evidence for HCV, low quality of evidence for hepatitis B virus).85 In addition, the  guidelines stated that, in adults with HCV, magnetic resonance-guided elastography has little or no increased diagnostic accuracy for identifying cirrhosis compared with VCTE in patients who have cirrhosis, and has lower diagnostic accuracy than VCTE in patients who do not have cirrhosis (very low quality of evidence). 

Chronic Liver Disease 

American College of Radiology
The 2017 American College of Radiology appropriateness criteria rated 1-dimensional transient elastography as a 7 (usually appropriate) for the diagnosis of liver fibrosis in patients with chronic liver disease.88 The criteria noted, “This procedure is less reliable in diagnosing liver fibrosis and cirrhosis in patients with obesity or ascites.” 

European Association for the Study of Liver Disease et al
The European Association for the Study of Liver Disease and the Asociacion Latinoamericana para el Estudio del Higado convened a panel of experts to develop clinical practice guidelines on the use of noninvasive tests to evaluate liver disease severity and prognosis, with results published in 2015.89 The publication provided a summary of the advantages and disadvantages of noninvasive techniques (serum biomarkers, imaging techniques). A summary of the joint recommendations for serum biomarkers and transient elastography is provided in Table 9.

Table 9. Recommendations for Serum Biomarkers and Transient Elastography

Biomarkers

Evidence Quality

Recommendation

"Serum biomarkers can be used in clinical practice due to high applicability (>95%) and good reproducibility."

High

Strong

"TE can be considered the non-invasive standard for the measure of LS"

High

Strong

"Serum biomarkers are well-validated for chronic viral hepatitis…. They are less well-validated for NAFLD not validated in other chronic kidney diseases."

High

Strong

"For the diagnosis of significant fibrosis a combination of tests with concordance may provide the highest diagnostic accuracy"

High

Weak

"All HCV patients should be screened to exclude cirrhosis by TE [or]… serum biomarkers.…"

High

Strong

"Non-invasive assessment including serum biomarkers or TE can be used as first line procedure for the identification of patients at low risk of severe fibrosis/cirrhosis"

High

Strong

"Follow-up assessment by either serum biomarkers or TE for progression of liver fibrosis should be used for NAFLD patients at a 3 year interval"

Moderate 

Strong 

HCV: hepatitis C virus; LS: liver stiffness; NAFLD: nonalcoholic fatty liver disease; QOE: quality of evidence; SOR: strength of recommendation; TE: transient elastography.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable. 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials    

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01789008

Transient Elastography in the Determination of Advanced Fibrosis in Alcoholic Liver Disease (FIBR-OH)

300

Aug 2017

Unpublished

NCT02569567

Comparison of Smart-Shear Wave Elastography and Transient Elastography (SMART)

105

Jun 2016 (ongoing)

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

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Coding Section

Code Number

Code Description

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
Proprietary test: HCV FibroSURE™, FibroTest™
Laboratory/Manufacturer: BioPredictive S.A.S

81599

Unlisted multianalyte assay with algorithmic analysis

84999

Unlisted chemistry procedure

88341

Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)

88342

Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure 

0002M

Liver disease, ten biochemical assays (ALT, A2-macroglobulin, apolipoprotein A-1, 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)
Proprietary test: ASH FibroSURE™
Laboratory/Manufacturer: BioPredictive S.A.S

0003M

Liver disease, ten biochemical assays (ALT, A2-macroglobulin, apolipoprotein A-1, 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)
Proprietary test: NASH FibroSURE™
Laboratory/Manufacturer: BioPredictive S.A.S

0014M

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
Proprietary test: Enhanced Liver Fibrosis™ (ELFTM) Test
Lab/Manufacturer: Siemens Healthcare
Diagnostics Inc/Siemens Healthcare Laboratory LLC

0166U

Liver disease, 10 biochemical assays (α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, AST, triglycerides, cholesterol, fasting glucose) and biometric and demographic data, utilizing serum, algorithm reported as scores for fibrosis, necroinflammatory activity, and steatosis with a summary interpretation
Proprietary test: LiverFASt™
Lab/Manufacturer: Fibronostics

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

10/02/2020 

Annual review, no change to policy intent. Updating coding. 

10/28/2019 

Annual review, updating policy verbiage to expand coverage for FibroTest, FibroSure and ELF. Expanding list of noncovered testing. Also adding medical necessity verbiage regarding magnetic resonance elastography (CPT 76391), previously considered investigational, will now have medical necessity criteria. Reformatting for clarity 

12/19/2018 

Updating with 2019 codes.  

11/19/2018 

Annual review, updating policy verbiage on laboratory testing for specificity. Adding investigational statement related to serum biomarkers. Also updating rationale and references. 

11/01/2017 

Annual review, no change to policy intent. Updating coding, rationale and references. 

04/24/2017 

Annual review, updating policy to allow limited medical necessity criteria for FibroScan. Updating background, description, rationale, category, review date and references. 

04/06/2016 

Annual review, no change to policy intent. 

01/04/2016

Added cpt code 81599. No other changes made.

10/01/2015 

Annual review, no change to policy intent. Updated title, background, description, rationale and references. Added coding.

11/25/2014 

Annual Review. No changes made to policy.

11/06/2013

Updated Title, Policy Verbiage, Rationale and References. Added Benefit Applications section.


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