Medical Policies - Radiology
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Vibration-controlled transient elastography (VCTE) (e.g., FibroScan) may be considered medically necessary to assess the degree of advanced liver fibrosis and cirrhosis in an individual with any of the following conditions:
• Hepatitis C,
• Hepatitis B,
• Chronic alcoholic liver disease, and
• All other chronic liver diseases.
Magnetic resonance elastography (MRE) may be considered medically necessary for individuals with non-alcoholic fatty liver disease (NAFLD) who have at least one of the following high-risk factors:
• Advanced age (65 years old or greater),
• Obesity (BMI 30 or higher),
• Alanine aminotransferase (ALT) greater than twice the upper limit of normal.
VCTE and MRE are considered experimental and investigational and/or unproven for all other indications.
The use of other ultrasound elastographic techniques, including but not limited to acoustic radiation force impulse imaging or real-time tissue elastography, for any indication is considered experimental, investigational or unproven.
Elastography is a noninvasive, ultrasound image technique that provides objective data to evaluate tissue elasticity or stiffness by measuring tissue displacement using compression. The technique employs external compression in order to induce strain inside the tissue that is scanned. Tissue compression produces strain or displacement within the tissue; therefore, the strain is smaller and harder in the malignant tissue than in the benign tissue. By measuring the tissue strain, tissue hardness can be estimated by differentiating between malignant and benign masses. The resulting strain image is called an elastogram. Each pixel on the elastogram denotes the estimated amount of strain the tissue experienced during the applied compression. (3)
There are various approaches to elastographic imaging, all of which consist of three basic steps: excitation (stress) application, tissue response (strain) measurement, and mechanical parameters estimation. (5) Clinical use of elastography is increasing, with applications including lesion detection and classification, fibrosis staging, treatment monitoring, vascular imaging and musculoskeletal applications. (1, 2) There is a concern that obesity can decrease the diagnostic accuracy which would potentially limit the usefulness of the test especially in countries where obesity and metabolic syndrome are common. (3)
There are several types of elastography techniques (4, 5):
1. Vibration-controlled transient elastography (VCTE), also known as transient elastography (TE), gives a quantitative one-dimensional image of tissue stiffness. It functions by vibrating the skin with a motor to create a passing distortion in the tissue (a shear wave), and imaging the motion of that distortion as it passes deeper into the body using a one-dimensional (1D) ultrasound beam. It then displays a quantitative line of tissue stiffness data. This technique is used mainly by the FibroScan system.
2. Acoustic radiation force impulse imaging (ARFI) uses ultrasound to create a qualitative 2-D map of tissue stiffness. It does so by creating a 'push' inside the tissue using the acoustic radiation force from a focused ultrasound beam. The amount the tissue along the axis of the beam is pushed down is reflective of tissue stiffness; softer tissue is more easily pushed than stiffer tissue. By pushing in many different places, a map of the tissue stiffness is built up.
3. Shear wave elasticity (SWE) uses focused beams of ultrasound energy from conventional transducers to produce movement within several microns at depths up to six centimeters below the ultrasound transducer. The technique results in low frequency shear waves in a plane perpendicular to tissue displacement. The speed of shear wave propagation is directly proportional to tissue elasticity, with faster speeds in tissue stiffness. Data is displayed in kilopascals (kPa) on color coded elasticity maps. This process provides a 2-dimensional map of tissue stiffness.
4. Real-time tissue elastography (RTE) evaluates reproducible differences in backscattered ultrasound signals that result from compression of tissues and uses color doppler to generate an image of tissue movement in response to the external vibrations.
5. Magnetic resonance elastography (MRE) is a pneumatic driver activated by a special MRE pulse sequence that performs velocity encoding through phase sensitization. The pulse sequence is sensitive to the transmission of waves through the tissue, and the data from the troughs and peaks is mathematically converted into parametric images that display tissue elasticity in kPa.
Although biopsy is the gold standard for assessment of fibrosis and cirrhosis in liver disease, there are multiple limitations, including all of the following:
TE offers the patient and physician a noninvasive alternative to measure and monitor fibrosis and cirrhosis.
Several devices have received U. S. Food and Drug Administration (FDA) approval for the use in elastography mode to include FibroScan, Sonixtech® Ultrasound Scanner, Sonosite MaXXTM ® Series Ultrasound system, GE LOGIQ E9 BT010® Diagnostic Ultrasound System, Diagnostic Ultrasound System Aplio mx® and Aixplorer. (6, 7, 8)
FibroScan® was cleared through the FDA 510(k) process in April 2013. FibroScan is indicated for noninvasive measurement of shear wave speed at 50 Hz in the liver. FibroScan uses transient elastography for the non-invasive measurement of liver shear wave speed. A mechanical vibrator produces low-amplitude elastic waves that travel through the skin and intercostal space into the liver. Ultrasound is used to track the shear wave and to measure its speed, which is correlated with the elasticity of the liver. According to the FDA, the shear wave speed may be used as an aid to clinical management of patients with liver disease. (6)
The FDA approved ARFI in 2013. It precisely focuses the ultrasound beam within the region of interest as it enhances a lesions border and size. (7) On November 13, 2008, Acuson S2000™, which provides ARFI, was cleared for marketing by the FDA through the 510(k) process, because it was substantially equivalent to a legally marketed predicate device marketed in interstate commerce prior to May 28, 1976. The intended uses are as follows: Fetal, Abdominal, Intraoperative, Pediatric, Small Parts, Transcranial, OB/GYN, Cardiac, Pelvic, Neonatal/Adult Cephalic, Vascular, Musculoskeletal, Superficial Musculoskeletal, and Peripheral Vascular applications. The system also provides the ability to measure anatomical structures and provide information to the clinician that may be used adjunctively with other medical data obtained by a physician for clinical diagnosis purposes. (8)
On June 17, 2010, Hi VISION 900 Diagnostic Ultrasound Scanner, which provides real-time TE, was cleared for marketing by the FDA through the 510(k) process, because it was substantially equivalent to a legally marketed predicate device marketed in interstate commerce prior to May 28, 1976. “The Hi VISION Preirus is intended for use by trained personnel (doctor, sonographer, etc.) for the diagnostic ultrasound evaluation of Abdominal, Cardiac, Intra- operative, Fetal, Pediatric, Small Organ, Peripheral vessel, Biopsy, Trans-rectal, Trans-vaginal, Musculoskeletal, Neonatal Cephalic, Adult Cephalic, Endoscopy, Intra-luminal, Gynecology, Urology and Laparoscopic clinical applications.” (9)
On August 12, 2009, AIXPLORER® Ultrasound System, which provides shear wave elastography (SWE), was cleared for marketing by the FDA through the 510(k) process, because it, too, was substantially equivalent to a legally marketed predicate device marketed in interstate commerce prior to May 28, 1976. It is intended for the following applications: “Abdominal, Small Organs, Musculoskeletal, Superficial Musculoskeletal, Vascular, and Peripheral Vascular.” (10)
In 2008, Nahon et al. assessed the accuracy of liver stiffness measurement (LSM) for the diagnosis of extensive fibrosis and cirrhosis in patients with alcoholic liver disease (ALD).
One hundred and seventy-four patients with ALD were enrolled in 4 liver units and underwent concomitant liver biopsy and LSM. Fibrosis was assessed using the Brunt et al. and the Chevallier et al. scoring systems. Steatosis and histological alcoholic hepatitis (HAH) were quoted in classes. Twenty-seven patients had inadequate biopsy or LSM. Distribution in 147 patients according to the Brunt score (median LSM) was: F1: n=13 (5.7 kilopascals [kPa]); F2: n=24 (8.3 kPa); F3: n=31 (17.5 kPa) and F4: n=79 (40.9 kPa) (P<0.0001). LSM was correlated with the amount of fibrosis according to the Chevallier score (r=0.70, P<0.0001). LSM was correlated to fibrosis stage (tau beta, 0.53; P<0.0001) and HAH (tau beta, 0.30; P<0.0001). In multivariate analysis, fibrosis was the only parameter correlated with LSM. The areas under the ROC curve were 0.94 and 0.87 for the diagnosis of extensive fibrosis (Brunt et al. score > or =3) and cirrhosis, respectively (threshold-values: 12.9 and 22.6 kPa). The study determined that LSM accurately assesses extensive fibrosis and cirrhosis in alcoholic patients. (11)
A comparative study to compare liver stiffness was performed in 2010 by Malik and colleagues. The study assessed transient elastography (TE), aspartate aminotransferase-to-platelet ratio index (APRI) score, aspartate aminotransferase (AST), alanine aminotransferase (ALT) ratio, hyaluronic acid (HA) and clinical signs to determine which modality performed best at identifying compensated cirrhosis. Patients undergoing evaluation at a single center were recruited and had clinical, serological, endoscopy, radiological imaging, LSM and liver biopsy. Patients were stratified into cirrhotic verses non-cirrhotic. In 404 patients (124 cirrhosis), TE was diagnostically superior to the other modalities yielding an area under the curve (AUC) 0.9 +/- 0.04 compared with HA (AUC 0.81 +/- 0.04: P < 0.05), clinical signs (AUC 0.74 +/- 0.04: P < 0.05), APRI score (AUC 0.71 +/- 0.03: P < 0.05) and AST/ ALT ratio (AUC 0.66 +/- 0.03: P < 0.05). The optimum cut-off for TE was 12 kilopascals (kPa) giving a sensitivity of 89% and specificity of 87% for cirrhosis. In 238 hepatitis C patients (87 cirrhosis), TE yielded an AUC 0.899 +/- 0.02 for cirrhosis and in 166 non-HCV patients (37 cirrhosis) the results were similar with an AUC 0.928 +/- 0.03; with TE being superior to HA, APRI scoring, AST/ALT and clinical signs for all etiologies of cirrhosis (P < 0.05 for all). Importantly, TE was statistically superior at identifying cirrhosis in 38 biopsies. TE accurately identified compensated cirrhosis; a liver stiffness of >12 kPa represents an important clinical measurement for the diagnosis of cirrhosis. (12)
In 2012, Cardoso et al. performed a direct comparison of diagnostic performance of TE for the assessment of liver fibrosis in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. A secondary analysis was performed to assess whether or not ALT levels would impact on the accuracy of TE. This cross-sectional, single center study included treatment-naïve patients with compensated chronic HBV or HCV infection, consecutively admitted between 2006 and 2008 for a liver biopsy and TE measurement on the same day. A total of 202 HBV patients and 363 HCV subjects were evaluated. Overall diagnostic accuracy of TE in the HBV group was comparable to that observed in HCV patients [area under the receiver-operating characteristics 0.867 ± 0.026 vs. 0.868 ± 0.019 for predicting F ≥ 2, P = 0.975; 0.902 ± 0.029 vs. 0.894 ± 0.020 for F ≥ 3, P = 0.820; and 0.935 ± 0.024 vs. 0.947 ± 0.027 for F4, P = 0.740 respectively]. TE exhibited comparable accuracies, sensitivities, specificities, predictive values and likelihood ratios in HBV and HCV groups. AUROC analysis showed no influence of ALT levels on the performance of TE in HBV individuals. ALT-specific cut-off values did not exhibit significantly higher diagnostic performances for predicting fibrosis in HBV patients with elevated ALT. In HBV patients, TE measurement accurately predicts the absence or presence of significant fibrosis, advanced fibrosis or cirrhosis and shows similar performances as compared to HCV patients. The use of TE cut-off values adjusted to ALT level did not improve performances for estimating liver fibrosis in HBV patients. (13)
In 2010, Wong and colleagues evaluated the diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the accuracy of transient elastography for the diagnosis of fibrosis and cirrhosis in patients with NAFLD and to study factors associated with discordance between transient elastography and histology. Two hundred forty-six consecutive patients from two ethnic groups had successful liver stiffness measurement and satisfactory liver biopsy specimens. The area under the receiver-operating characteristics curve (AUROC) of transient elastography for F3 or higher and F4 disease was 0.93 and 0.95, respectively, and was significantly higher than that of the aspartate aminotransferase-to-alanine aminotransferase ratio, aspartate aminotransferase-to-platelet ratio index, FIB-4, BARD, and NAFLD fibrosis scores (AUROC ranged from 0.62 to 0.81, P < 0.05 for all comparisons). At a cutoff value of 7.9 kPa, the sensitivity, specificity, and positive and negative predictive values for F3 or greater disease were 91%, 75%, 52%, and 97%, respectively. Liver stiffness was not affected by hepatic steatosis, necroinflammation, or body mass index. Discordance of at least two stages between transient elastography and histology was observed in 33 (13.4%) patients. By multivariate analysis, liver biopsy length less than 20 mm and F0-2 disease were associated with discordance. The study concluded that the use of transient elastography is accurate in most NAFLD patients. Unsatisfactory liver biopsy specimens rather than transient elastography technique account for most cases of discordance. With high negative predictive value and modest positive predictive value, transient elastography is useful as a screening test to exclude advanced fibrosis. Liver biopsy may be considered in NAFLD patients with liver stiffness of at least 7.9 kPa. (14)
Leung et al. (2013) studied shear wave elastography (SWE) for assessing liver fibrosis in chronic hepatitis B and compared its performance with TE. The study analyzed 226 patients with liver biopsy correlation and 171 healthy patients. SWE of liver, TE of liver, and SWE of spleen was 0.86, 0.80, and 0.81 for fibrosis (≥F1 stage); 0.88, 0.78, and 0.82 for moderate fibrosis (≥F2 stage); 0.93, 0.83, and 0.83 for severe fibrosis (≥F3 stage); and 0.98, 0.92, and 0.84 for cirrhosis (F4 stage). SWE of the liver showed significantly higher accuracy than TE of the liver and SWE of the spleen in all fibrosis stages. SWE of the spleen showed similar accuracy with TE of liver. Combination SWE of liver and spleen to predict fibrosis staging showed diagnostic accuracy which was not improved compared with SWE of the liver alone. SWE of the liver had a higher success rate than TE of liver (98.9% vs 89.6%). Prevalence of discordance in at least two stages with liver histologic staging was 10.2% (23 of 226) for SWE of the liver and 28.2% (58 of 206) for SWE of the spleen. It was determined that SWE provides more accurate correlation of liver elasticity with liver fibrosis stage compared with TE, especially in identification of stage F2 or greater. (15)
Cassinotto et al. completed a study of 321 patients with chronic liver disease who underwent liver biopsies from April 2010 to May 2012 to compare the diagnostic performance of acoustic radiation force impulse (ARFI) imaging elastography with that of FibroScan® M and XL probes and FibroTest in the staging of fibrosis in patients with chronic liver disease. Liver disease was caused by viral hepatitis (n = 136), alcoholic or nonalcoholic steatohepatitis disorders (n = 113), or some other disease (n = 72). In each patient, liver stiffness was evaluated with ARFI elastography using M and XL probes and a FibroTest was done within 1 month prior to liver biopsy. Histologic staging of liver fibrosis served as the reference standard. LSM failure rates were 11.2% with the M probe (36 of 321 patients), 2.3% with the XL probe (6 of 260 patients), and 0% with ARFI elastography (0 of 321 patients). Unreliable results with ARFI elastography were more frequent in obese patients (those with a body mass index of 30 kg/m2 or more) (42 of 86 patients [48.8%] vs 34 of 235 patients. No significant difference was found between ARFI elastography and the M probe in the diagnosis of cirrhosis (area under the receiver operating characteristic curve, or severe fibrosis; however, the M probe demonstrated better results in the diagnosis of moderate fibrosis. No significant difference was found between ARFI elastography and the XL probe in the diagnosis of moderate fibrosis, severe fibrosis, or cirrhosis. The diagnostic performance of ARFI elastography improved when it was applied in nonobese patients (Az of ARFI for cirrhosis and severe fibrosis = 0.92 and 0.91, respectively, in nonobese patients [P = .0002] and 0.63 and 0.63, respectively, in obese patients [P < .0001]). The authors determined that ARFI elastography is reliable in the assessment of liver fibrosis in patients with chronic liver disease, especially nonobese patients). (16)
Potthoff et al. (2013) studied the influence of different frequencies and insertion depths on the diagnostic accuracy of liver elastography by ARFI imaging. ARFI is an innovative elastography for staging of liver fibrosis.Diagnostic accuracy of different probes was evaluated at different insertion depths. This was a prospective study; 89 chronic HCV infected patients underwent ARFI elastography using both available probes (c-ARFI: C4-1-MHz; l-ARFI: L9-4 MHz) in comparison to FibroScan®. Variability of ARFI elastography at different insertion depths was systematically evaluated in 39 patients (44%). According to FibroScan® elastography, 32 patients (36%) presented with liver cirrhosis, 23 patients (26%) had significant fibrosis, and 34 patients (38%) had no significant fibrosis. Results of both probes were correlated to each other and to FibroScan®.In patients with significant fibrosis or with cirrhosis, mean values by 1-ARFI were significantly higher than by c- ARFI. For detection of liver cirrhosis, AUROC was 0.97 for c-ARFI (cut-off level 1.72 m/s) and 0.90 for l-ARFI (cut-off 2.04 m/s).Correlation coefficients of c-ARFI with FibroScan® were highest at an insertion depth of 5-6cm and at 3-4cm for l-ARFI. It was determined, ARFI elastography with the linear probe verses the convex probes showed comparable validity and accuracy in the estimation of liver stiffness. The linear probe gave higher ARFI values. The most accurate insertion depth was 5-6 cm for c-ARFI and 3- 4 cm for l-ARFI indicating that measurements should not be performed close to the liver capsule. (17)
In 2013, Sirli, R, et al. completed a retrospective study to assess the feasibility of TE and the factors associated with failed and unreliable LSM, in patients with chronic liver diseases. Included were 8218 consecutive adult patients with suspected chronic liver diseases. In each patient, LSM’s were performed with a FibroScan device, with the M probe. Failure of TE measurements was defined if no valid measurement was obtained after at least 10 shots and unreliable if fewer than 10 valid shots were obtained. From the 8218 patients, failed and unreliable LSMs were observed in 29.2% of cases.In univariant analysis, the following risk factors were associated with failed and unreliable measurements: age over 50 years, female gender, BMI > 27.7 kg/m, weight > 77 kg and height < 162 cm. In multivariate analysis, all the factors mentioned were independently associated with the risk of failed and unreliable measurements.If all the negative predictive factors were present (woman, older than 50 years, with BMI > 27.7 kg/m, heavier than 77 kg and shorter than 162 cm), the rate of failed and unreliable measurements was 58.5%. In obese patients, the rate of failed and unreliable measurements was 49.5%. Failed and unreliable LSMs were observed in 29.1% of patients.Female gender, older age, higher BMI, higher weight, and smaller height were significantly associated with failed and unreliable LSMs. (18)
Kim et al. (2013) evaluated the diagnostic accuracy of magnetic resonance elastography (MRE) as a method to help diagnose clinically substantial fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) and, by using MRE as a reference standard, to compare various laboratory marker panels in the identification of patients with NAFLD and advanced fibrosis. This retrospective study involved 325 patients with NAFLD, who were identified by imaging characteristics consistent with steatosis in a prospective database that tracks all MRE examinations. Six laboratory-based models of fibrosis were compared with MRE results as well as fibrosis stage from liver biopsy results. The area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value of each data set were compared. Among 325 patients with NAFLD with MRE data, there were 142 patients who underwent liver biopsy within 1 year of MRE. When comparing MRE results with liver biopsy results, the best cutoff for advanced fibrosis (stage F3–F4, 46 [32.4%] of 142) was 4.15 kilopascals (AUROC = 0.954, sensitivity = 0.85, specificity = 0.929). This cutoff value identified 104 patients with advanced fibrosis (32.0% of 325 patients). The FIB-4 score (AUROC = 0.827) and NAFLD fibrosis score (AUROC = 0.821) had the best diagnostic accuracy for advanced fibrosis, with high negative predictive values (NAFLD fibrosis score = 0.90 and FIB-4 score = 0.899). In conclusion, MRE is a useful diagnostic tool for detecting advanced fibrosis in NAFLD. Of the laboratory-based methods, the NAFLD fibrosis and FIB-4 scores can most reliably detect advanced fibrosis. (19)
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. (20) 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. (21) 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. (22) 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%. (23) Yin et al. (2016) retrospectively analyzed 1377 consecutive MRE examinations performed between 2007 and 2010 for patients with various chronic liver diseases. (24) MRE had a success rate of 94% and highly reproducible measurements (r=0.972, p<0.001). BMI was not associated with success.
In October 2014, ECRI Institute completed a health technology assessment on FibroScan TE for determining optimal candidates for hepatitis C pharmacotherapy. ECRI performed a comprehensive search in PubMed for studies that were published between January 1, 2009, and September 3, 2014; EMBASE search focused on conference papers and abstracts published between January 1, 2012, and September 3, 2014. ECRI identified 1 systematic review, 31 studies examining FibroScan’s ability to detect significant fibrosis and cirrhosis (24 journal publications and 8 conference abstracts), 1 study that examined the impact of FibroScan measurements on patient management, 1 study examining FibroScan’s ability to predict patient response to treatment, 4 studies examining FibroScan’s ability to predict later complications, including liver cancer (2 journal publications and 2 conference abstracts), and 8 reviews. In summary, evidence from the review of 12 publications (1 systematic review and meta-analysis, 8 journal publications and 3 conference proceedings) suggest that FibroScan can diagnose liver fibrosis stages in patients with chronic HCV infection and can separate stages F0 to F1 from stages F2 to F4 (significant fibrosis) and F4 (cirrhosis) from all other stages when compared with gold-standard liver biopsy. For distinguishing stage F0 to F2 from F3 and F4, fewer studies reported data separately according to these staging categories; however, those that did, reported that FibroScan can separate stages F3 and F4 from earlier stages. These abstracts do not provide a clear picture of the actual diagnostic characteristics of the FibroScan. Additional information is needed on the means and confidence intervals for sensitivity, specificity, and negative and positive predictive values for FibroScan measurements at each fibrosis stage. Additional information is also needed on how these values differ across populations with various comorbidities, across differences in the number of patients in each stage of fibrosis, and across changes in the kPa thresholds used to define fibrosis stages. Evidence from the ECRI Institute review of nine publications (7 journal publications and 2 conference proceedings) suggests that failure to obtain a FibroScan measurement or obtaining unreliable FibroScan results varies from 3% to 32% primarily due to patient obesity. There are 4 ongoing observational studies that are expected to report between 2014 and 2019. Whether these studies will provide additional information about differentiating between F0/F2 stages and F3/F4 stages is not clear from the protocol descriptions. (25)
There is extensive literature on the use of transient elastography to gauge liver fibrosis and cirrhosis. Brener et al. (2015) performed a health technology assessment summarizing many of the systematic reviews. (26) 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 were included in the Brener health technology assessment, summarizing more than 150 primary studies. (27-40) 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). (41) 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. The overall sensitivity and specificity for cirrhosis including all diseases (65 studies; cutoffs range, 9.2-26.5 kPa) were 89% (95% confidence intervals [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.
In 2014, Hong et al. reported results of a meta-analysis of real-time tissue elastography (RTE) for staging fibrosis in multiple diseases. (42) Thirteen studies (total N=1347 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. (43) They included 15 studies (total N=1626 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.
In March 2013, Moon et al. evaluated the diagnostic performance of gray-scale ultrasound and elastography in differentiating benign and malignant thyroid nodules. This was an institutional review board–approved retrospective study. A total of 703 solid thyroid nodules in 676 patients (mean age, 49.7 years; range, 18–79 years) were included; there were 556 women (mean age, 49.5 years; range, 20–74 years) and 120 men (mean age, 50.7 years; range, 18–79 years). Nodules with marked hypoechogenicity, poorly defined margins, microcalcifications, and a taller-than-wide shape were classified as suspicious at grayscale ultrasound. Findings at elastography were classified according to the Rago criteria and the Asteria criteria. The diagnostic performances of gray-scale ultrasound and elastography were compared. For comparison between the diagnostic performances of gray-scale Ultrasound and the combination of gray-scale Ultrasound and elastography, three sets of criteria were assigned: criteria set 1, nodules with any suspicious grayscale Ultrasound feature were assessed as suspicious; criteria set 2, Rago criteria were added as suspicious features to criteria set 1; and criteria set 3, Asteria criteria were added as suspicious features to criteria set 1. The diagnostic performances of gray-scale Ultrasound elastography (USE) with Rago criteria, and elastography with Asteria criteria, and odds ratios (ORs) with 95% confidence intervals for predicting thyroid malignancy were compared using generalized estimating equation analysis. Of 703 nodules, 217 were malignant and 486 were benign. Sensitivity, negative predictive value (NPV), and OR of gray-scale ultrasound for the 703 nodules were 91.7%, 94.7%, and 22.1, respectively, and these values were higher than the 15.7% and 65.4% sensitivity, 71.7% and 79.1% NPV, and 3.7 and 2.6 ORs found for elastography with Rago and Asteria criteria, respectively. Specificity, positive predictive value, and accuracy for criteria set 1 were significantly higher than those for criteria sets 2 and 3 for most of the nodule subgroups that were considered. Elastography alone, as well as the combination of elastography and gray-scale ultrasound, showed inferior performance in the differentiation of malignant and benign thyroid nodules compared with gray-scale US features; elastography was not a useful tool in recommending fine-needle aspiration biopsy. (44)
Vidal-Casariego et al. studied the accuracy of ultrasound elastography in the diagnosis of thyroid cancer in a low-risk population. Stiffness has been associated to malignancy in the prostate and breast, as well as thyroid. The aim was to assess the accuracy of elastography in a population with low risk of malignancy. 128 consecutive patients with nodular goiter were recruited. Elastography and ultrasound-guided FNA were performed. When malignancy was suspected by cytology, surgery was recommended. Thyroid nodules were classified by elastography according the criteria described by Ueno, and an alternative classification. Sensitivity, specificity, predictive values, and odds ratio were calculated. Most patients were female, aged 56.1 year, with single nodule (52.0%) or multinodular goiter (45.6%), and a few thyroiditis (2.4%). The majority of nodules were mostly elastic. FNA found 86% of benign nodules, 9.3% of indeterminate, and 4.7% possibly malignant. After surgery, 3 malignant nodules were confirmed, all of them being papillary carcinomas. All the malignant nodules were mostly elastic, as well as 75% of indeterminate nodules. Low values of sensitivity and specificity were found for elastic nodules being benign and hard nodules malignant. In a low-risk population for thyroid cancer, elastography lacks accuracy for the diagnosis of malignant nodules. (45)
Kumm and Szabunio (2010) evaluated the application and diagnostic performance of elastography for the characterization of breast lesions in patients referred for biopsy. Subjects referred for ultrasound-guided biopsy of sonographically apparent breast lesions were included in this study. The Hitachi Hi-Vision 900 ultrasound® was used to generate index test results for elastography scoring (ES) and for strain ratio (SR) measurement. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were determined using pathologic results from 14-gauge core needle biopsy as the reference standard. A total of 310 lesions in 288 patients were included in this study. Out of 310 lesions, 223 (72 %) were benign and 87 (28 %) were malignant.Sensitivity was 0.76 for ES and 0.79 for SR. Specificity was 0.81 for ES and 0.76 for SR. The PPV was 0.60 for ES and 0.57 for SR; the NPV was 0.90 for ES and 0.90 for SR. The SRvalues for malignant lesions were significantly higher (median ratios of10.5 and 2.7, respectively,p < 0.001). The authors concluded that while the initial clinical performance of elastography imaging shows potential to reduce biopsy of low-risk lesions, a large-scale trial addressing appropriate patient selection, diagnostic parameters, and practical application of this technique is needed before widespread clinical use. (46)
In 2012, Landoni and colleagues developed a quantitative method for breast cancer diagnosis based on elastosonography images in attempt to reduce unnecessary biopsies. The proposed method was validated by correlating the results of quantitative analysis with the diagnosis assessed by histopathologic examination. A total of 109 images of breast lesions (50 benign and 59 malignant) were acquired with the traditional B-mode technique and with elastographic modality. Images in Digital Imaging and Communications in Medicine (DICOM) format were exported into software, written in Visual Basic, especially developed to perform this study. The lesion was contoured and the mean grey value and softness inside the region of interest (ROI) were calculated. The correlations between variables were investigated and receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic accuracy of the proposed method. Pathologic results were used as standard reference. Both the mean grey value and the softness inside the ROI resulted statistically different at the t-test for the 2 populations of lesions (i.e., benign versus malignant): p <0.0001. The area under the curve (AUC) was 0.924 (0.834 to 0.973) and 0.917 (0.826 to 0.970) for the mean grey value and for the softness respectively. The authors concluded that quantitative elastosonography is a promising ultrasound technique in the detection of breast cancer; but large prospective trials are needed to determine if quantitative analysis of images can help to overcome some pitfalls of this method. (47)
Sadigh et al. (2013) reported a meta-analysis of the diagnostic performance of USE versus B-mode ultrasound (USB) across size ranges of breast masses. Five studies were analyzed involving 1,412 breast masses. Included studies were performed in Turkey, South Korea, Romania, Germany, and China. For breast masses <10 mm, the sensitivity/specificity of USE and USB were 76 %/93 % and 95 %/68 %, respectively. For masses 10–19 mm, sensitivity/specificity of USE and USB were 82 %/90 % and 95 %/67 %, respectively. For masses >19 mm, sensitivity/specificity of USE and USB were 74 %/94 % and 97 %/55 %, respectively. The authors noted that the sensitivity and specificity of each of these techniques for characterizing breast masses were not significantly different among masses with sizes of less than 10 mm, 10–19 mm, and more than 19 mm. Subgroup analysis of masses more than 29 mm demonstrated similar result. The authors indicate that none of the studies clearly stated whether the reference standard interpretation was performed without the knowledge of index test (i.e., USE) results. It was also unclear whether relevant clinical data were available to radiologists when they interpreted the USE and USB images. An additional limitation was the inclusion of uncontrolled trial data for analysis. (48)
In 2017, Blank and colleagues published a systematic review and meta-analysis. The authors reported measured elasticities of benign and malignant breast pathologies from SWE, quantitatively confirmed the effect of the selected ROI on these measures and tested the hypothesis that a metric of heterogeneity based on the mean and maximum elasticity can improve specificity of diagnosis. The elasticity of benign, malignant and specific pathologic states were reported from 22 publications encompassing 2,989 patients, identified from a structured search of literature from May to September 2015. A total of 12 articles were included in a meta-analysis that grouped results by the method of ROI selection to discriminate between different pathologies. These researchers observed a significant correlation between the method of selection of ROI for malignant mean (p < 0.001) and maximum (p = 0.027) elasticity, but no correlation with benign measures. They defined a quantitative heterogeneity parameter, the "stiffness gradient", computed from the mean and maximum measured elasticity. The stiffness gradient out-performed the current standard maximum elasticity metric in stratifying malignancy risk by a margin of 15 % for the partial ROI, and 42 % for the maximized ROI. An anecdotal example of improved differentiation using the stiffness gradient on pathology-specific lesions was also provided. The authors concluded that these results quantitatively indicated that the method of ROI selection in SWE not only has a significant impact on the resulting mean reported elasticity of a lesion, but may provide some insight into lesion heterogeneity. They stated that these findings suggested that further exploration of quantitative heterogeneity is needed to improve the specificity of diagnosis. (49)
Practice Guidelines and Position Statements
American Association for the Study of Liver Diseases (AASLD) / Infectious disease society of America (IDSA)
AASLD/IDSA (2014, updated 2017) states the most efficient approach to fibrosis assessment is to combine direct biomarkers and vibration-controlled transient liver elastography. A biopsy should be considered for any patient who has discordant results between the 2 modalities that would affect clinical decision making. Liver elastography can provide instant information regarding liver stiffness at the point-of-care but can only reliably distinguish cirrhosis from non-cirrhosis. Since persons with known or suspected bridging fibrosis and cirrhosis are at increased risk of developing complications of advanced liver disease, they require more frequent follow up. (50)
American College of Radiology (ACR)
The ACR Appropriateness Criteria® for nonpalpable mammographic findings (excluding calcifications) note that elastography is being evaluated as a way to increase the specificity of ultrasound, especially regarding evaluation and management of solid masses. (51)
The 2017 ACR Appropriateness Criteria® for chronic liver disease rated 1-dimensional transient elastography as a 7 (usually appropriate) for the diagnosis of liver fibrosis in patients with chronic liver disease. (57) The criteria noted, “This procedure is less reliable in diagnosing liver fibrosis and cirrhosis in patients with obesity or ascites.”
National Comprehensive Cancer Network (NCCN)
The National Comprehensive Cancer Network (NCCN) practice guideline for colon cancer and breast cancer screening does not indicate elastography as a diagnostic modality in their clinical guidelines. (52, 53)
The NCCN guideline for thyroid carcinoma states FNA is the procedure of choice for evaluation of suspicious thyroid nodules. (54)
National Institute for Health and Care Excellence (NICE)
NICE published a guideline for the use of TE for the diagnosis and management of chronic hepatitis B in children, young people and adults (2013, updated October 2017). NICE recommends that TE is offered as the initial test for liver disease in adults newly referred for assessment. Specific TE results are noted at which point a liver biopsy is recommended. (55)
World Health Organization (WHO)
In 2016, WHO updated their first guideline issued in 2014 for the screening, care, and treatment of persons with hepatitis C infection. WHO notes that FibroScan, if available, can be used to assess liver stiffness. This recommendation was formulated assuming that liver biopsy was not a feasible option. FibroScan, which is more accurate than APRI and FIB4, may be preferable in settings where the equipment is available and the cost of the test is not a barrier to testing. (56)
American Gastroenterological Association (AGA)
In 2017, the AGA published a guideline on the role of elastography in the evaluation of liver fibrosis. (58) Recommendations were as follows:
• “In patients with chronic hepatitis C, the AGA recommends VCTE, if available, rather than other nonproprietary, noninvasive serum tests (APRI, FIB-4) to detect cirrhosis. (Grade: Strong recommendation, moderate quality evidence.)
• In patients with chronic hepatitis C, the AGA suggests a VCTE cutoff of 12.5 kPa to detect cirrhosis. (Grade: Conditional recommendation, low-quality evidence.)
• In noncirrhotic patients with HCV who have achieved SVR [sustained virologic response] after antiviral therapy, the AGA suggests a post-treatment vibration controlled transient elastography cutoff of 9.5 kPa to rule out advanced liver fibrosis. (Grade: Conditional recommendation, very low-quality evidence.)
• In patients with chronic hepatitis B, the AGA suggests VCTE rather than other nonproprietary noninvasive serum tests (i.e., APRI and FIB-4) to detect cirrhosis. (Grade: Conditional recommendation, low-quality evidence.)
• In patients with chronic hepatitis B, the AGA suggests a VCTE cutoff of 11.0 kPa to detect cirrhosis. (Grade: Conditional recommendation, low-quality evidence.)
• The AGA makes no recommendation regarding the role of VCTE in the diagnosis of cirrhosis in adults with NAFLD. (Grade: no recommendation --- knowledge gap.)
• In patients with chronic alcoholic liver disease, the AGA suggests a VCTE cutoff of 12.5 kPa to detect cirrhosis. (Grade: Conditional recommendation, low-quality evidence.)
• In patients with suspected compensated cirrhosis, the AGA suggests a vibration controlled transient elastography cutoff of 19.5 kPa to assess the need for esophagogastroduodenoscopy to identify high risk esophageal varices. (Grade: Conditional recommendation, low-quality evidence.)
• In patients with suspected chronic liver disease undergoing elective nonhepatic surgery, the AGA suggests a VCTE cutoff of 17.0 kPa to detect clinically significant portal hypertension to inform preoperative care. (Grade: Conditional recommendation, low-quality evidence.)
• In adult patients with chronic hepatitis C, the AGA suggests using VCTE rather than MRE for detection of cirrhosis. (Grade: Conditional recommendation, very low-quality evidence.)
• In adults with NAFLD and a higher risk of cirrhosis, the AGA suggest using MRE, rather than VCTE, for detection of cirrhosis. (Grade: Conditional recommendation, low quality evidence.) High-risk populations are NAFLD with advanced age, obesity, particularly central adiposity, diabetes, alanine elevated >2x upper limit of normal with an estimated cirrhosis prevalence of 30% (typically seen in a referral setting); low-risk population are those with NAFLD and signs of fatty liver on imaging only and an estimated cirrhosis prevalence of ≤5% (typically seen in a primary care setting).”
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in the table below.
Summary of Key Trials
Transient Elastography in the Determination of Advanced Fibrosis in Alcoholic Liver Disease (FIBR-OH).
Aug 2017 (ongoing)
Comparison of Smart-Shear Wave Elastography and Transient Elastography (SMART).
Jun 2016 (unknown)
NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.
Summary of Evidence
Literature search through January 31, 2018 identified multiple studies that evaluate elastography technology for use in various medical conditions to include the liver, breast, thyroid, abdominal and the musculoskeletal system.
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) and society guidelines support. 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 randomized controlled trials (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 (MRE), 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. However due to lower false-positive rates, the American Gastroenterological Association recommends MRE over vibration-controlled transient elastography in individuals with non-alcoholic fatty liver disease in a specific subset of patients deemed to be at high risk for cirrhosis.
With the exception of liver fibrosis and cirrhosis, minimal studies were identified for the use of all elastography radiologic methods (e.g., magnetic resonance elastography, real-time transient elastography, acoustic radiation force impulse imaging, transient elastography) for breast and thyroid nodules. Small cohorts were noted and some research appears promising for elastography as a potential diagnostic tool for staging of breast and thyroid nodules although research is still in the initial stages of research. Large scientifically controlled studies are needed in order to validate the diagnostic performance compared to other diagnostic tests currently available (i.e., biopsy).
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|6/1/2018||Document updated with literature review. The following changes were made to Coverage: 1) Reworded medical necessity statement on transient elastography; 2) Added conditional coverage for magnetic resonance elastography; 3) Split the experimental/investigational/unproven statement into two separate statements, one to address when the conditional criteria for vibration-controlled transient elastography and magnetic resonance elastography is not met, and the other to address other indications and types of elastography. References 20-24, 26-43, 49, 57-59 added.|
|12/1/2016||Reviewed. No changes.|
|3/1/2015||Document update with literature review. The following was added to coverage: Transient elastography (e.g., FibroScan) once every six months may be medically necessary to assess the degree of liver fibrosis and cirrhosis in an individual with chronic liver disease, when a liver biopsy has not been performed within six months. Entire document revised.|
|1/1/2014||New medical document. Elastography, by any method, is considered experimental, investigational, and/or unproven.|