Nonalcoholic fatty liver disease (NAFLD) now

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1 AMERICAN ASSOCIATION FOR THE STUDY OFLIVERD I S E ASES CONCISE REVIEW HEPATOLOGY, VOL. 64, NO. 6, 2016 Noninvasive Imaging Methods to Determine Severity of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis William N. Hannah Jr. and Stephen A. Harrison Nonalcoholic fatty liver disease (NAFLD) is now the most common form of liver disease in developed countries, with an estimated prevalence of 20%-30% and increasing to as high as 90% in diabetics. As the rates of NAFLD continue to rise in parallel with those of the obesity pandemic, it is increasingly important to differentiate those patients with the highest risk of progression to fibrosis and cirrhosis. In fact, those patients with nonalcoholic steatohepatitis (NASH) and fibrosis are at the greatest risk of progression to advanced disease, cirrhosis, and hepatocellular cancer and are more likely to develop liver-related mortality. Thus, it is critically important to distinguish between NASH and non-nash NAFLD. Whereas liver biopsy remains the gold standard for staging of disease, complications of this procedure and other well-recognized limitations make it impractical for widespread use given the overall NAFLD disease burden. Noninvasive imaging modalities are increasingly being utilized to evaluate and stage NAFLD in patients with such a wide spectrum of disease. In this article, the role of these new and promising noninvasive imaging modalities to assess disease severity in NAFLD are reviewed. (HEPATOLOGY 2016;64: ) Nonalcoholic fatty liver disease (NAFLD) now represents the most common form of liver disease in developed countries, with an estimated prevalence of 20%-30% and increasing to 70% in obese individuals and 90% in diabetics. (1,2) With NAFLD representing the hepatic manifestation of metabolic syndrome, the rates of NAFLD continue to rise as obesity reaches pandemic proportions. Of those with NAFLD, the prevalence of biopsy-proven nonalcoholic steatohepatitis (NASH) has been estimated at 12.2% in a prospective community cohort and up to 56% in diabetic patients. (3,4) Importantly, individuals with NASH and fibrosis have the greatest risk of progression to advanced disease, cirrhosis, and hepatocellular cancer. (5,6) It is estimated that 70%-75% of patients with NAFLD will have either isolated steatosis or non- NASH NAFLD, which is defined as steatosis with mild amounts of lobular and/or portal inflammation. (3,7) For those patients with isolated steatosis, there is generally very little progression to fibrosis and liver-related complications with no increased risk of death compared to the general population. (8-10) Similarly, the majority of patients with non-nash Abbreviations: ARFI, acoustic radiation force impulse; AUROC, area under the receiver operator curve; BMI, body mass index; CAP, controlled attenuation parameter; HCC, hepatocellular carcinoma; HS, hepatic steatosis; IQR, interquartile range; kpa, kilopascals; LSM, liver stiffness measurement; mhz, megahertz; MMRI, multiparametric MRI; MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio; PDFF, proton density fat fraction; pswe, point quantification shear wave elastography; SWE, shear wave elastography; US, ultrasound; USG, ultrasonography; VCTE, vibration controlled transient elastography. Received November 3, 2015; accepted June 16, The views expressed are those of the authors and should not be construed as official views of the United States Air Force, United States Army, or Department of Defense. Published This article is a U.S. Government work and is in the public domain in the USA. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Dr. Harrison advises and is on the speakers bureau for Gilead, Merck, and Alexion. He consults for Fibrogen, NGM, and Medivation. He advises Pfizer, Intercept, and Nimbus. He is on the speakers bureau for AbbVie. 2234

2 HEPATOLOGY, Vol. 64, No. 6, 2016 HANNAH AND HARRISON NAFLD will have a relatively benign course with very low rates of progression to liver-related death. In fact, patients with biopsy-proven NASH are 6 times more likely to develop liver-related mortality over 20 years than those with non-nash NAFLD. (11) For patients with NASH, however, fibrosis progression rates have been estimated to be 1 stage every 7 years, significantly higher than patients with non-nash NAFLD. (12) Fibrosis stage is a strong predictor of overall mortality, cardiovascular disease, infectious diseases, hepatocellular carcinoma (HCC), and cirrhosis. (5) Among fibrosis stages, the presence of advanced fibrosis, including bridging and cirrhosis, has the highest risk of mortality followed by portal inflammation, diagnosis of NASH,andthepresenceofballooning. (13) In adults awaiting liver transplantation in the United States, NASH is now the second-leading indication, surpassing alcoholic liver disease and lagging only behind hepatitis C. (14) Thus, distinguishing between NASH and non- NASH NAFLD is critically important. Liver biopsy is the gold standard for the diagnosis and histological assessment of NAFLD. The risks of liver biopsy, however, are not inconsequential. Additionally, sampling error, invasiveness, and inter- and intraobserver variability make liver biopsy less than ideal for all patients, especially given the high world-wide prevalence of NAFLD. Because of these limitations, noninvasive imaging tests to assess NAFLD, particularly those patients with NASH, and the severity of fibrosis are being developed. This article reviews the role of promising and new noninvasive imaging modalities in the diagnosis and management of NAFLD as well as the advantages and limitations of each (Table 1). Ultrasound Conventional ultrasound (US) is the most common method for the qualitative assessment of hepatic steatosis (HS) because of its ready availability and low cost. On US, a steatotic liver appears brighter than surrounding structures because of the increased soundwave scatter and attenuation from lipid-laden vesicles. (15) In a meta-analysis of 28 studies using US to evaluate HS, the mean sensitivity of ultrasonography (USG) for the identification of HS compared with liver biopsy ranged from 73% to 91%. (16) For mild steatosis (0%-10%) on liver biopsy, however, sensitivity dropped to 62.2%-81.2%. In 118 patients with known NASH, Tobari et al. evaluated the ability of US to detect steatosis. (17) Overall, the sensitivity of detecting mild (10%-29% hepatocytes containing fat) to severe steatosis (30%-69%) was 79.7%. (17) In 63 patients with severe steatosis (70%), the sensitivity was 98.4%. The ability to detect steatosis in patients with NASH was significantly limited by the presence of advanced fibrosis. In fact, the sensitivity of detecting moderateto-severe steatosis in NASH with only mild fibrosis was 100%, but in almost one quarter of NASH patients with advanced fibrosis, US could not detect even moderate-to-severe steatosis. Conventional USG is not able to discriminate between HS, fibrosis, inflammation, or NASH. (18,19) Thus, US is very good at detecting severe steatosis, but coexisting fibrosis and inflammation may produce false negatives. Furthermore, US is significantly limited by both inter- and intraobserver reliability. (20) Vibration Controlled Transient Elastography US-based vibration controlled transient elastography (VCTE), marketed as the FibroScan (Echosens, Paris, France), is the most validated and commonly used elastography method used worldwide. (21) This technique measures the velocity of a low-amplitude shear wave as it propagates through the liver in a prespecified area of interest and converts the wave velocity into liver stiffness. (22) A systematic review of VCTE in patients with NAFLD by Kwok et al. involved nine studies and ARTICLE INFORMATION: From the Department of Medicine, San Antonio Military Medical Center, JBSA Fort Sam Houston, TX. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Stephen A. Harrison, M.D. Chief of Hepatology, Department of Medicine, Division of Gastroenterology San Antonio Military Medical Center 3551 Roger Brooke Drive JBSA Fort Sam Houston, TX Tel: stephen.a.harrison.mil@mail.mil 2235

3 HANNAH AND HARRISON HEPATOLOGY, December 2016 TABLE 1. Noninvasive Imaging Modalities for NAFLD Severity Imaging Advantages Disadvantages Severity Assessment US Ready availability Low cost Provides evaluation of liver architecture VCTE Short processing time (<10 minutes) Ambulatory clinic setting Immediacy of results CAP Immediate assessment of steatosis Ambulatory clinic setting Simultaneous LSM for fibrosis pswe Readily available Immediate results Failure rates less than VCTE or SWE Allows for simultaneous sonographic imaging of the liver SWE Immediate assessment Ambulatory clinic setting Excellent intraobserver reliability (0.95) (45) Allows for simultaneous sonographic imaging of the liver MRE Not affected by obesity Simultaneous MRI for liver architecture, carcinoma, and MRS for steatosis Can be coupled with PDFF for assessment of HS MMRI Can be accomplished in 20 minutes No additional hardware needed No contrast Not affected by obesity Simultaneous MRI for liver architecture and carcinoma screening Only qualitative assessment of HS Limited by inter- and intraobserver variability Reliable LSM only 75% in obese individuals (despite XL probe) (32) False positives (ascites, congestion) Data excluded patients from US Does not reliably differentiate between steatosis grades (38) Similar shortcomings as VCTE in obese patients Failed or unreliable measurements in 19% (24) Does not allow for quantification or assessment of steatosis Limited to one clinical study in NALFD patients (24) Can explore larger field of view than pswe LSM failures in 15% of patients (24) Reliable results in only 73% of patients with BMI 30 kg/m 2(24) Costly Time-consuming Requires MRI facility May be inaccurate in acute inflammation or iron overload Cannot be used in some patients with implantable devices Requires MRI facility Single, small pilot study Results not specific to NAFLD patients (52) Cannot distinguish between inflammation and fibrosis Cannot be used in some patients with implantable devices Good at detecting moderate steatosis (30%) (16) Cannot discriminate between HS, fibrosis, inflammation, or NASH Excellent in diagnosing fibrosis stage 3 and 4 (NPV 90%) (32,34) May be less accurate in diagnosing fibrosis in patients with moderate steatosis >33% (25,28) Overall significant increase in CAP across steatosis grades Possible role for screening for NAFLD in diabetics when coupled with VCTE (4) Specificity (85%) in detecting significant fibrosis stage 2 (40) Underperformed SWE and VCTE for fibrosis stage 2 in head-to-head study (24) Statistically better diagnostic performance than pswe for fibrosis stage 2 (24) Similar diagnostic accuracy as VCTE (24) Can accurately detect advanced fibrosis and cirrhosis (47) Detection of NASH is limited (47) May be more accurate than VCTE for the diagnosis of advanced fibrosis in one small pilot study (51) Results correlated highly with fibrosis, steatosis May be superior to US-based (52) elastography in ability to discriminate no fibrosis from any degree of fibrosis (52) Abbreviation: NPV, negative predictive value. 1,047 patients. (23) Overall, VCTE was good in diagnosing fibrosis stage 3 (85% sensitivity, 82% specificity) and excellent for stage 4 (92% sensitivity, 92% specificity), but only moderate accuracy for fibrosis stage 2 (79% sensitivity, 75% specificity). Based on the work of Kwok and others, (23,24) VCTE appears useful as a good screening test for cirrhosis with a 90% specificity for fibrosis stage 2 or greater in patients with a positive test as defined by specific cut-off values. However, the probability of correctly diagnosing early fibrosis stages drops considerably, even with a positive test, given the declining specificity. Furthermore, negative test results do not completely exclude cirrhosis, with some studies showing false-negative results even for fibrosis stage 4. (25-27) A recently published study by Cassinotto et al. evaluated the diagnostic accuracy of shear wave elastography (SWE), VCTE, and point quantification shear wave elastography (pswe) in 291 patients with NAFLD. (24) For VCTE, optimal cut-off values were determined to predict significant fibrosis. For fibrosis stage 3, the liver stiffness measurement (LSM) cutoff ranged from 8.2 (90% sensitivity) to 12.5 kilopascals (kpa; 90% specificity) and area under the 2236

4 HEPATOLOGY, Vol. 64, No. 6, 2016 HANNAH AND HARRISON receiver operator curve (AUROC) 0.86 ( ). For fibrosis stage 4, the LSM cutoff ranged from 9.5 (90% sensitivity) to 16.1 kpa (90% specificity) and AUROC 0.87 ( ). These cut-off values are similar to those described in the Kwok meta-analysis, but unfortunately, validated and widely accepted cutoff values for VCTE in NAFLD patients are lacking. Concerns about the diagnostic accuracy of VCTE have been raised because of the effect of HS on LSM. For example, Gaia et al. evaluated 219 patients with chronic hepatitis B and NAFLD for the reliability of VCTE for detection of fibrosis. (25) In the subgroup of 72 NAFLD patients with moderate steatosis (>33%) and advanced fibrosis, LSM values were lower than expected and similar to fibrosis stages 1 and 2. Petta et al. very recently assessed the impact of steatosis severity on LSM values and on VCTE accuracy for the diagnosis of fibrosis in 253 patients with NAFLD. (28) Paradoxically, patients with steatosis (66%) at liver biopsy had higher LSM values that led to higher falsepositive LSM results. Thus, in patients with a high degree of steatosis, there are conflicting data with respect to the accuracy of VCTE in diagnosing fibrosis in NAFLD, and further study is necessary to clarify this issue. Major challenges to the successful use of VCTE in clinical practice have been generally limited to the rate of failure (no valid measurements) or unreliable results as defined as interquartile range (IQR)/LSM 0.30 in patients with LSM 7.1 kpa. (29) Most commonly, this is a result of obesity to include subcutaneous and visceral fat and operator inexperience, (30,31) but other reasons include recent ingestion of food, ascites, and heart failure. In the recent Cassinotto study, LSM failures occurred in 14.4% of patients with VCTE, and unreliable results were observed in 8.9% of cases. (24) In response to these limitations in obese patients, a newer FibroScan XL probe was developed for use in obese patients. The probe emits a lower central US frequency and explores a deeper region of interest to overcome the difficulties caused by excess subcutaneous fat, which attenuates the transmission of shear waves and measurement of their propagation by US. Wong et al. evaluated the performance of the XL probe on 193 consecutive patients with NAFLD. (32) Reliable measurements were obtained in 75% of all NAFLD patients and 65% of those with body mass index (BMI) 30 kg/m 2. Wong et al. also demonstrated that both the sensitivity and specificity of the XL probe in NAFLD patients for stage 3 fibrosis or greater was 78%. LSM measurements for the XL probe correlated well with the M probe, though the XL probe generated lower LSM values for the same stage of fibrosis. As such, optimal cut-off values for VCTE using the traditional probe cannot be readily transferred to the XL probe and may require an entirely separate set of cutoff values. Nevertheless, for the majority of NAFLD patients, the XL probe appears to eliminate VCTE failure in 90% of patients and facilitates reliable LSM in significantly more obese patients that the traditional probe. Similar to traditional B-mode elastography techniques, benefits of VCTE include the short processing time, which can be less than 5 minutes, ready availability in the outpatient clinic setting, and immediacy of test results. Limitations to the use of VCTE in patients with NAFLD are significant given the high rates of failed or unreliable LSM in obese patients. However, the use of the FibroScan XL probe appears to overcome this limitation in the majority of NAFLD patients. (32) VCTE has the potential to monitor NAFLD progression, but in a study of patients with various chronic liver diseases, interoperator variability and patient-related factors contribute to significant variations in LSM over time that are not related to disease progression. (33) Collectively, the data suggest that VCTE is best used to exclude severe fibrosis and cirrhosis with a high negative predictive value approaching 90%. (32,34) The diagnostic accuracy of VCTE in patients with NAFLD in the United States remains uncertain given that there are no published studies that included NAFLD patients from the United States. Controlled Attenuation Parameter The controlled attenuation parameter (CAP) is a novel method for grading of HS by measuring the degree of US attenuation by hepatic fat by using a process based on simultaneous VCTE. When using the traditional M probe, CAP measures the US attenuation at the center frequency of VCTE at 3.5 megahertz (mhz) in the same region of interest. It is evaluated using the same radiofrequency data as that used for LSM, and results are measured in db/m over a range of db/m. (35) With the exception of one study, all of the published literature on CAP has relied solely on the FibroScan M probe. Thus, CAP has been subject to the same limitations as VCTE, and failure rates may be as high as 7.7%. (36) Sasso et al. very recently published a small pilot study that successfully implemented CAP with the XL 2237

5 HANNAH AND HARRISON HEPATOLOGY, December 2016 probe. (37) Reproducibility of the CAP with the M and XL probes was similar and both demonstrated good performance. Despite these promising results, further evaluation in patients exclusively requiring the use of the XL probe and validation in larger studies is necessary before CAP can be recommended in certain obese and overweight patients. In the largest prospective trial to date, de Ledinghen et al. evaluated CAP for the diagnosis of steatosis in 261 patients with NAFLD. (38) The CAP of patients was distributed to each steatosis grade: S , S , and S db/m. (38) Patients with S2 and S3 steatosis have significantly higher CAP than those with less steatosis (P < 0.001), with the AUROC of CAP to detect S2 and S3 being 0.80 and 0.66, respectively. A cut-off value of 310 db/m for S2 corresponded to a negative predictive value to exclude S2 steatosis of 59%. Interestingly, at this cutoff, correct assessment of steatosis S2-S3 was 86.3%, 99% in NASH patients, and 65.6% in non-nash NAFLD patients. The best cutoff for S3 steatosis was 311 db/m with a negative predictive value to exclude S3 steatosis of 88% and a positive predictive value of 43%. Discordance of at least 1 grade between CAP and histology occurred in 31% of patients, though the discordance rate between S2-S3 and CAP in patients > 310 db/m was only 15%. In this study, NAFLD patients with a greater degree of steatosis had higher CAP values than those with less steatosis. Unfortunately, CAP values overlapped significantly between adjacent steatosis grades, thereby limiting the ability to adequately discriminate the degree of steatosis. Even at optimal cut-off values, the specificity for steatosis grades S2 and S3 is lower than both proton density fat fraction (PDFF) and magnetic resonance spectroscopy (MRS) and similar to conventional USG. Based on two small studies in patients with NALFD, CAP appears to be an additional noninvasive tool for detection of significant (S2-S3) HS, and it provides immediate assessment with simultaneous LSM for fibrosis in NAFLD patients. (38,39) In patients with known NAFLD, CAP may add significant information on the degree of steatosis beyond the LSM obtained by VCTE, particularly in patients with NASH. (38) Unfortunately, CAP does not appear effective for discriminating between closely related grades of HS. Kwok et al. recently demonstrated the effectiveness of VCTE and CAP in screening diabetic patients with NAFLD, (4) suggesting that CAP, when coupled with VCTE, has potential as a simple screening method for patients with suspected NAFLD. Whereas optimal cut-off values for CAP in NAFLD differ slightly in the published studies, the work by de Ledinghen provides the most rigorous evaluation of cut-off values in NAFLD patients. (38) The major limitation to CAP is the high failure rate, though the recent work by Sasso et al. may ultimately improve failure rates, (37) and further validation of the CAP with the XL probe is needed. Though early studies are encouraging, further large, prospective trials are needed to better define the role of CAP in the evaluation of patients with NAFLD, NASH, and non-nash NAFLD. pswe Another imaging technique being utilized in the evaluation of NAFLD is pswe, which, in addition to SWE, involves the use of acoustic radiation force impulse (ARFI) technology. An ARFI pulse generates short-duration acoustic impulses in a small region of interest that cause mechanical excitation of liver tissue. As the shear waves propagate, the US machine is used to monitor the shear wave propagation. This energy transfer and tissue displacement over time and different locations can then be used to calculate a shear wave speed in meters per second. This velocity can be converted into kilopascals through Young s modulus. pswe shares similar advantages to VCTE in that it is readily available in the clinical setting and test results can be immediately available. As with other US-based imaging modalities that integrate elastography, patients who require simultaneous sonographic evaluation of the liver, ascites assessment, or HCC screening may be better candidates for pswe or SWE over VCTE in order to avoid multiple studies. Unfortunately, pswe does not allow for assessment or quantification of steatosis, which can be accomplished with VCTE when combined with CAP. To evaluate the diagnostic efficacy of pswe in patients with NAFLD, Liu et al. completed a systematic review of seven studies for a total of 723 patients who underwent pswe. (40) From their meta-analysis, the summary sensitivity was 80.2% in detecting significant fibrosis, which was defined as fibrosis stage 2. The summary specificity was determined to be 85.2%, and the diagnostic odds ratio (OR) of pswe in detecting significant fibrosis was (95% confidence interval, ; P ). Based on these data, the researchers concluded that pswe was moderately 2238

6 HEPATOLOGY, Vol. 64, No. 6, 2016 HANNAH AND HARRISON accurate in detecting significant fibrosis. The Liu metaanalysis did not assess optimal cut-off values for pswe. Cassinotto et al. compared the diagnostic performance of pswe with VCTE and SWE in 291 patients with NAFLD. (24) In this study, pswe performed equally well for fibrosis stage 3 and fibrosis stage 4, but underperformed SWE and VCTE for fibrosis stage 2. To date, this is the first comparative trial to evaluate the efficacy of these three modes of elastography in NAFLD patients, and the results are similar to previous studies that have looked at individual imaging methods. (23,41) When coupled with a similar trial evaluating pswe with VCTE and SWE in patients with chronic liver disease, (42) there appears to be a slight advantage for SWE for early-stage fibrosis. For the majority of patients, however, it appears that pswe, SWE, and VCTE can all reliably detect significant fibrosis. Unfortunately, 29% of patients in the Cassinotto study had fibrosis stage <2. For these patients, none of these modes of elastography can successfully identify patients with NAFLD, and, as a result, one third of the patients in this study would require additional evaluation. Optimal cut-off values for pswe for the diagnosis of fibrosis were assessed. For fibrosis stage 2, the LSM ranged from 0.95 to 1.32 m/s, with 56%-90% sensitivity, 36%-90% specificity, and AUROC For fibrosis stage 3, the LSM ranged from 1.15 to 1.53 m/s, with 59%-90% sensitivity, 63%-90% specificity, and AUROC For fibrosis stage 4, the LSM ranged from 1.3 to 2.04 m/s, with 44%- 90% sensitivity, 67%-90% specificity, and AUROC Though these cut-off values are similar to other published studies, there are no well-established cutoffs for pswe in NAFLD patients. Cassinotto et al. observed failure rates of 0.7%, but unreliable LSM results occurred in 18.2% of cases. Thus, failure rates were lower for pswe than SWE or VCTE (both P < ), but compared to other studies utilizing VCTE with the XL probe, the rate of unreliable LSM in obese patients undergoing pswe was similar or higher. (43,44) Further investigation in NAFLD patients is necessary to confirm these findings. SWE One additional method that relies on elastography in current use to evaluate liver stiffness is SWE, commonly referred to as supersonic shear imaging based on one of four systems commercially available that uses two-dimensional SWE with an ARFI impulse. Similar to pswe, SWE is built on conventional USG, but instead of emitting a single shear wave, SWE emits several ARFI pulses at increasing depths and differing frequencies. The net result is that SWE allows the asynchronous evaluation of the velocity of multiple shear waves over a wide range of frequencies. Previous work has demonstrated an excellent intraobserver reproducibility of 0.95, though novice operators may require a learning curve to obtain these reproducible measurements. (45) A potential advantage of SWE is the ability to perform measurements over a wider region of interest and thereby reduce sampling errors. Cassinotto et al. performed the only study to evaluate SWE in NAFLD patients. (24) Overall, SWE had statistically better diagnostic performance for fibrosis stage 2 than pswe with AUROC of 0.85 versus 0.76 (P ), but similar diagnostic accuracy to VCTE (AUROC, 0.85 vs. 0.83; P 5 0.5). LSM failures occurred in 15% of patients, whereas unreliable results occurred in 7.2% of cases. These rates are very similar to VCTE, with obesity having the greatest impact. In fact, reliable results were obtained in approximately 90% of patients with a BMI <30 kg/ m 2, but only 73% of patients with a BMI 30 kg/m 2. Optimal LSM cut-off values for SWE were: fibrosis stage 2, kpa, with 71%-90% sensitivity, 50%-90% specificity, and AUROC ; fibrosis stage 3, kpa, with 71%-91% sensitivity, 71%-90% specificity, and AUROC ; fibrosis stage 4, kpa, with 58%-90% sensitivity, 72%-90% specificity, and AUROC SWE has essentially the same advantages as pswe, but it also has the advantage of being able to explore a larger field of view or specific region of interest. It is worth noting that LSM failures were more frequent in obese individuals with a BMI 30 kg/m 2. (24) Both Cassinotto (42) and Leung (46) have suggested that SWE may be considered as a screening test for patients with milder liver fibrosis stages, though further rigorous trials are needed to confirm this as well as the applicability to patients with NAFLD. Magnetic Resonance Elastography Magnetic resonance elastography (MRE) is one final option to assess hepatic fibrosis in patients with NAFLD utilizing the principles of elastography. MRE uses a modified phase-contrast method to image the 2239

7 HANNAH AND HARRISON HEPATOLOGY, December 2016 propagation of the shear wave in the liver parenchyma. Additionally, PDFF measurement is an option that can be added to magnetic resonance imaging (MRI) scanners to quantitatively assess HS. The diagnostic accuracy of MRE for staging liver fibrosis was recently analyzed in a systematic review. Sing et al evaluated nine studies that included 232 patients with NAFLD. (47) For each fibrosis stage, the investigators calculated mean AUROC: stage 1 (0.86), stage 2 (0.87), stage 3 (0.90), and stage 4 (0.91). When stratified by sex, obesity, and degree of inflammation, similar diagnostic performance was observed. In another study, Loomba et al. prospectively evaluated the diagnostic accuracy of MRE in the detection of advanced fibrosis in 117 patients with biopsy-proven NAFLD. (48) For discriminating advanced fibrosis stage 3-4 from fibrosis stage 0-2, the AUROC was This high degree of accuracy likely reflects that adjacent fibrosis stages were combined in the analysis, though the ability to diagnosis advanced fibrosis is clinically relevant given that these patients have the highest risk of disease progression. With a threshold of >3.63 kpa, MRE demonstrated a positive predictive value of 68% and a negative predictive value of 97%. Therefore, at this cut-off value, MRE demonstrates an excellent ability to exclude significant fibrosis. This threshold value reflects a calculation of the magnitude of the complex shear modulus and can be compared with other US-based elastography measures by multiplying by a factor of 3. (49) For the diagnosis of NASH, however, the AUROC was Collectively, the results of these studies suggest that MRE can accurately detect advanced fibrosis and cirrhosis in patients with NAFLD, though the accuracy for detection of NASH is limited and lower than a previous retrospective study by Chen el al. (50) Imago et al. recently compared VCTE and MRE for the staging of liver fibrosis as well as compared CAP to PDFF for grading HS in a small sample of only 142 patients with NAFLD. (51) For MRE, potential LSM cut-off values were determined for each stage of fibrosis: F 1 (2.5 kpa, AUROC 0.80, sensitivity 75%, and specificity 85.7%; F 2 (3.4 kpa, AUROC 0.89, sensitivity 87.3%, and specificity 85%); F 3(4.8kPa,AUROC 0.89, sensitivity 74.5%, and specificity 86.9%); F4 (6.7 kpa, AUROC 0.97, sensitivity 90.9, and specificity 94.5%). Compared to VCTE, there was significantly greater accuracy for liver fibrosis stage 2 (P ) and 4 (P ). In this study, CAP and PDFF correlated reasonably well with HS grades; however, the diagnostic accuracy of MRI-based PDFF for each grade of steatosis was superior to CAP: S 1(P ), S 2 (P ), and S3 (P ). Unfortunately, there are no large, prospective trials comparing MRE to US-based elastography in NAFLD. Though the Imago study does compare MRE to VCTE, (51) the small sample size precludes making firm recommendations. Based on the available data, MRE appears comparable to US-based methods for significant fibrosis, but further study is needed to determine whether it is more accurate or can identify earlier stages of fibrosis in NAFLD. MRE can be coupled with MRI for structural evaluation and HCC screening, though US can be used similarly. MRE can utilize PDFF for HS assessment. Additionally, MRE performance is not affected by obesity, and the area measured in the liver is large, potentially avoiding sampling error. MRE readings may be inaccurate in conditions such as acute inflammation and iron overload, which can cause signal-to-noise limitations. The fact that MRE is costly, time-consuming, and not readily available may make it less suitable for routine screening of NAFLD patients in clinical practice and may make US-based methods more practical. Ultimately, MRE may be best suited for morbidly obese patients in whom ultrasound-based elastography fails or in whom detailed liver imaging is necessary. Multiparametric Magnetic Resonance Imaging Imaging of the liver utilizing multiparametric MRI (MMRI; Liver MultiScan; Perspectum Diagnostics, Oxford, UK) is a quantitative assessment method that utilizes T1, T2, and PDFF to quantify iron deposition, liver fibroinflammatory disease, and HS. MRI also provides information on liver architecture, structural detail, and other anatomical findings. To evaluate the effectiveness of this imaging modality, Banerjee et al. conducted a prospective trial comparing quantitative MRI techniques to liver biopsy in 79 unselected patients referred for routine hepatology care. (52) With respect to liver fibrosis, T1 mapping corrected for iron (corrected T1 or ct1) strongly correlated with increased liver fibrosis with significant difference among all stages, except between mild and moderate fibrosis. When NASH was assessed separately, corrected T1 correlated closely with fibrosis stage and identified patients with fibrosis, with an AUROC of Similarly, hepatic lipid content correlated strongly with semiquantitative steatosis scores using rapid 2240

8 HEPATOLOGY, Vol. 64, No. 6, 2016 HANNAH AND HARRISON magnetic resonance spectroscopy (MRS) measurements. In identifying Brunt steatosis score of 0 from a Brunt score 1, MRS has an AUROC of Elevated iron concentrations drastically lower measurements of T1; thus, the researchers developed a method to remove this bias. For hepatic iron content, T2* mapping distinguished patients with stainable iron with an AUROC of In this sole pilot study, MMRI was able to identify and quantify fibrosis, steatosis, and iron content in a single magnetic resonance scan in approximately 20 minutes. Furthermore, this imaging modality was not affected by obesity or ascites. Unfortunately, results are limited by a small sample size and included a general spectrum of patients referred for liver biopsy. From the available data, it is not possible to compare the results to US elastography for each stage of fibrosis, though the overall ability to discriminate no fibrosis from any degree of fibrosis appears superior. The correlation coefficient observed for the collagen proportionate area in those patients with NASH, though significant, was noticeably less than that those patients with viral hepatitis. Larger studies involving subpopulations of patients of chronic liver disease are needed to validate the effectiveness of this imaging modality, especially in NAFLD. Corrected T1 measurements could not be accomplished in 2 patients with massive hemosiderosis, and MRI may not be feasible in certain patient populations with implantable medical devices with metal, which may malfunction or heat up and cause injury. In addition, MMRI cannot distinguish between inflammation from fibrosis given that both increase corrected T1, which is similar to US elastography. Despite these potential limitations, MMRI is a novel imaging modality and may play a future role in the assessment of steatosis and fibrosis in patients with NAFLD. Summary The burden of chronic liver disease attributed to NAFLD is increasing in parallel with the obesity pandemic. Current data suggest that NAFLD affects as many as 280 million obese individuals. (53,54) Fortunately, the majority of these patients will have a relatively benign course, but identifying the 25%-30% of patients with NASH from those with non-nash NAFLD is vital. Given that liver biopsy is impractical in this large demographic of patients, imaging techniques to assess fibrosis and steatosis are an important noninvasive adjunct. Currently, imaging modalities using elastography have gained wide acceptance with a number of good potential options. The most validated imaging modality in use for patients with NAFLD is VCTE. Utilizing the XL probe, 90% of patients can overcome the limitations of this technology. Unfortunately, VCTE is best suited to exclude significant fibrosis and cirrhosis given its high negative predictive value, but lesser accuracy for lower stages of fibrosis. Additionally, none of the major trials included patients from the United States. CAP is a technique that can be performed simultaneously with VCTE and appears promising for the assessment of HS. In patients with NAFLD, CAP does not reliably differentiate between closely related steatosis stages. Combined with VCTE, it may play a role in screening obese and diabetic patients for the presence of NAFLD, though further trials are needed to validate this. pswe, MRE, and SWE are three additional elastography techniques to evaluate liver fibrosis. In the single study to evaluate SWE in NAFLD patients, SWE has statistically better performance for fibrosis stage 2 than pswe, but similar diagnostic accuracy to VCTE. Limited clinical data suggest that SWE may better differentiate early stage fibrosis and may potentially play a role in screening patients with NAFLD. Both pswe and SWE have the advantage of utilizing traditional ultrasound equipment. pswe demonstrates similar efficacy to VCTE. MRE appears more accurate at assessing significant liver fibrosis (stage 2) than VCTE in one small clinical trial in NAFLD patients, but more-rigorous study is needed to confirm this finding. Last, MMRI appears to be a new imaging technique to detect and quantify fibrosis and steatosis in a small proof-of-principle trial. Larger studies in subpopulations of chronic liver disease are needed to validate its effectiveness. REFERENCES 1) Barrera F, George J. The role of diet and nutritional intervention for the management of patients with NAFLD. Clin Liver Dis 2014;18: ) Leite NC, Villela-Nogueira CA, Pannain VL, Bottino AC, Rezende GF, Cardoso CR, et al. Histopathological stages of nonalcoholic fatty liver disease in type 2 diabetes: prevalences and correlated factors. Liver Int 2011;31: ) Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140:

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