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Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease
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Download the PDF here
Download the PDF here
Detecting Liver Disease: Two Imaging Methods Go Head to Head
Nonalcoholic fatty liver disease, or NAFLD, is on the rise. Driven in part by obesity and diabetes, this chronic disease can progress to liver cirrhosis and cancer. To better prevent and treat NAFLD, we need to be better at diagnosing it, says Rohit Loomba, MD, director of the NAFLD Research Center at UC San Diego Health.
The problem is that, at the moment, the only real way to diagnose NAFLD and other liver problems is with a biopsy - an invasive procedure that comes with its own risks.
Loomba and colleagues are looking for noninvasive alternatives. In their latest study, the team compared magnetic resonance imaging (MRI) and ultrasound-based techniques head-to-head for their accuracy in detecting liver fibrosis (scar tissue) and steatosis (fat buildup). They used these dueling techniques to examine the livers of 100 patients with NAFLD, with their biopsies for reference.
In round one, Loomba and team looked for fibrosis, comparing magnetic resonance elastrography vs. transient elastography (TE). In round two, they looked for steatosis in these patients, comparing MRI-based proton density fat fraction analysis vs. TE-based controlled attenuation parameter.
The results were published October 27, 2016 in Gastroenterology. Check out the paper here. PAPER BELOW COMMENTARY (Spoiler alert: the MRI-based techniques won both rounds!)
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summary in journal
Magnetic Resonance Elastography Is More Accurate Than Ultrasound-Based Transient Elastography in the Identification of Liver Fibrosis and Steatosis in Nonalcoholic Steatohepatitis
In a cross-sectional, single-center study of 104 adults undergoing liver biopsy for nonalcoholic steatohepatitis, magnetic resonance elastography with proton density fat fractionation was more accurate in detecting any fibrosis and steatosis than ultrasound-based transient elastography with controlled attenuation parameter.
Nonalcoholic fatty liver disease encompasses a broad spectrum of severity ranging from benign hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and cancer. At present, the current gold standard for diagnosis of nonalcoholic steatohepatitis is liver biopsy. However, this invasive method is limited by sampling error, variability in agreement in pathologic interpretation,and the risk of procedural complications. In this issue of Gastroenterology, Park etal (with an editorial by Thomas Karlas etal) report a cross-sectional study of 104 consecutive adults in a single US tertiary care center who underwent magnetic resonance elastography and ultrasound-based transient elastography (Fibroscan M and XL probe) before liver biopsy for suspected nonalcoholic fatty liver disease. They found that magnetic resonance elastography, with an area under the receiver operating curve of 0.82 (95% CI, 0.74-0.91), was significantly more accurate for diagnosis of any fibrosis (stage 1-4) compared with transient elastography, with an area under the receiver operating curve of 0.67 (95% CI, 0.56-0.87; P for difference= .0116; Figure1). In addition, assessment of magnetic resonance-based proton density fat fraction, with an area under the receiver operating curve of 0.99 (95% CI, 0.98-1.00), was significantly more accurate for diagnosis of any steatosis (grades 1-3) compared withtransient elastography-based controlled attenuation parameter, with an area under the receiver operating curve of 0.85 (95% CI, 0.75-0.96; P for difference= .009). Although limited by its cross-sectional, single-center design, these findings corroborate results reported in Japanese cohorts and suggest that magnetic resonance-based techniques are superior to transient elastography for the accurate, noninvasive assessment of fibrosis and steatosis in nonalcoholic fatty liver disease. Further studies are needed to compare the longitudinal predictive value and cost-effectiveness of these modalities before clinical recommendations can be offered.
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Editorial
Collaboration, Not Competition: The Role of Magnetic Resonance, Transient Elastography, and Liver Biopsy in the Diagnosis of Nonalcoholic Fatty Liver Disease
Gastroenterology Feb 2017 -THOMAS KARLASDivision of Gastroenterology and Rheumatology -DAVID PETROFFClinical Trial Centre -JOHANNES WIEGANDDivision of Gastroenterology and RheumatologyUniversity of LeipzigLeipzig, Germany
See "Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease" by Park CC, Nguyen P, HernandezC, etal, on page598. PAPER BELOW
The global obesity pandemic necessitates characterization of nonalcoholic fatty liver disease (NAFLD) in an extremely large and growing number of patients. This disease subsumes hepatic fat, inflammation, and fibrosis. Fibrosis is of particular interest, being the strongest predictor of mortality,1, 2 and noninvasive techniques for assessing its severity are becoming part of routine care, at least in Asia and Europe.3 As we endeavor to understand NAFLD more fully, steatosis quantification has become increasingly successful, although we are stillstruggling to understand its clinical implications.4, 5Nonalcoholic steatohepatitis (NASH) is a strong indicator of disease progression; until now, however, only liver biopsies were sufficiently reliable for diagnosing inflammatory activity.6
In this month's issue of Gastroenterology, Park etal7 compared 2 major noninvasive approaches, magnetic resonance and transient elastography (TE), in biopsy-proven NAFLD patients. Fibrosis was staged using magnetic resonance elastography (MRE)- and TE-based liver stiffness measurements and steatosis was graded with proton density fat fraction (PDFF) and the TE-based controlled attenuation parameter (CAP). This interesting study was the first to do so using an important TE probe combination (so-called M and XL probes), appropriate to an obese cohort. The authors concluded that MRE and PDFF are more accurate than TE and CAP for diagnosing fibrosis and steatosis, respectively.
A head-to-head comparison of this sort is necessary and certainly useful, but only part of the picture. There are various requirements and needs to be considered, and one cannot optimize all of them with a single approach.
⋅ a.The clinical need is risk stratification, so long as effective therapeutic options are available. "Risk" means progression of liver disease and, finally, liver-related and overall mortality.
⋅ b.The huge number of NAFLD patients who might be considered for screening necessitates a low-threshold point-of-care technique that should be inexpensive and easy to handle.
⋅ c.Existing infrastructure and resources need to be exploited to their best potential.
NAFLD diagnosis currently requires proof of steatosis, which relies on imaging techniques in clinical practice.8 Toaddress the diagnosis of the huge number of putative patients, studies of serum and anthropometry-based approaches are already underway.9 Similar strategies can also be used for further risk stratification because they are related to clinical outcomes.10 Biopsy is not viable for the many patients who then qualify for in-depth evaluation with higher specificity. Without question MRE/PDFF and TE/CAP could help to close this gap and a sophisticated discussion of their merits and drawbacks can be found in Friedrich-Rust etal.11 MRE is not yet as well evaluated as TE12 and the complex data acquisition and processing implies that standardization across different centers presents challenges. A recent comparable paper to that of Park etal was also able to show that MRE/PDFF is more accurate than TE/CAP in 142 NAFLD patients,4 but the very different cutoffs for staging fibrosis suggest that the conclusions require further verification. The European Association for the Study of the Liver guidelines recently proposed an algorithm based on liver enzymes and ultrasound imaging to select patients for specialist referral and assessment of disease severity.13 This algorithm can be used either by hepatologists or by other physicians treating NAFLD patients. Future guidelines will have to find the appropriate place for MRE/PDFF and TE/CAP in patient management also considering cost and logistics, which vary between health care systems.
The diagnostic properties of different options will certainly play a role, which shows the importance of research such as that published here by Park etal7 or by Imajo etal.4 TE and CAP cannot differentiate adjacent stages of fibrosis and steatosis with high precision, but potentially provide high negative predictive values for excluding advanced disease with respectable throughput. Use of MRE/PDFF and TE/CAP in clinical practice relies on harmonization, where important steps have been taken for TE liver stiffness measurement14, 15 and are underway for CAP,16 but with limited evidence for pure NAFLD cohorts.
NAFLD has been recognized as a distinct etiology for 2 decades now, but specific treatment has not gone much beyond lifestyle intervention.8, 13 As new pharmaceutical agents are developed, clinical endpoints must be defined and tested. The relatively slow progression of the disease means that surrogate endpoints will probably be most appropriate during early phases of drug development. MRE/PDFF and TE/CAP have yet to prove themselves in this regard, but are promising. In particular, repeated frequent observations can be performed with noninvasive techniques, but not with biopsy. The objective quantification on continuous scales would enable such studies to detect small changes, not discernible in histologic grading and staging. However, within the spectrum of NAFLD, NASH seems to forebode later complications,2 but effective noninvasive methods for diagnosing hepatic inflammation are still lacking, and liver biopsy remains the reference standard.17
To recapitulate, MRE/PDFF and TE/CAP will certainly both have a role to play in management of NAFLD patients and drug development. Park etal have published an important comparison that will help to find precisely how to use each approach to its best advantage, though there are aspects of the study that warrant critical discussion. These include a transparent presentation of why many patients are missing from the main comparison of steatosis results and thoughts on the meaning and relevance of steatosis grade S0 for the NAFLD etiology. There are gaps to be filled before either of the above options can be used optimally and some may prove to be serious obstacles.6 Biopsy is clearly inappropriate for screening, but remains the reference for diagnosis, especially of NASH, and for endpoint prediction. It must, however, be kept in mind that histologic assessment, MRE/PDFF, and TE/CAP evaluate distinct aspects of "steatosis" and "fibrosis": percentage of affected hepatocytes and distribution of extracellular matrix proteins on the one hand, and physical properties like fat molecule resonance spectra, tissue stiffness, and the attenuation of an ultrasound signal, on the other. The clinical relevance of each should be tested separately. At the moment, we definitely need "two to tango"18-biopsy and noninvasive techniques-to further develop the active field of NAFLD and NASH.
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Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease
Feb 2017 Gastroenterology -Charlie C. Park,1 Phirum Nguyen,1 Carolyn Hernandez,1 Ricki Bettencourt,1 Kimberly Ramirez,1Lynda Fortney,1 Jonathan Hooker,2 Ethan Sy,2 Michael T. Savides,1 Mosab H. Alquiraish,1Mark A. Valasek,3 Emily Rizo,1 Lisa Richards,1 David Brenner,1,4 Claude B. Sirlin,2 andRohit Loomba1,4,5
1Nonalcoholic Fatty Liver Disease Research Center, Department of Medicine, University of California at San Diego, La Jolla,California; 2Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, California;3Department of Pathology, University of California at San Diego, La Jolla, California; 4Division of Gastroenterology, Departmentof Medicine, University of California at San Diego, La Jolla, California; and 5Division of Epidemiology, Department of Family andPreventive Medicine, University of California at San Diego, La Jolla, California
Background & Aims
Magnetic resonance imaging (MRI) techniques and ultrasound-based transient elastography (TE) can be used in noninvasive diagnosis of fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a prospective study to compare the performance of magnetic resonance elastography (MRE) vs TE for diagnosis of fibrosis, and MRI-based proton density fat fraction (MRI-PDFF) analysis vs TE-based controlled attenuation parameter (CAP) for diagnosis of steatosis in patients undergoing biopsy to assess NAFLD.
Methods
We performed a cross-sectional study of 104 consecutive adults (56.7% female) who underwent MRE, TE, and liver biopsy analysis (using the histologic scoring system for NAFLD from the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System) from October 2011 through May 2016 at a tertiary medical center. All patients received a standard clinical evaluation, including collection of history, anthropometric examination, and biochemical tests. The primary outcomes were fibrosis and steatosis. Secondary outcomes included dichotomized stages of fibrosis and nonalcoholic steatohepatitis vs no nonalcoholic steatohepatitis. Receiver operating characteristic curve analyses were used to compare performances of MRE vs TE in diagnosis of fibrosis (stages 1-4 vs 0) and MRI-PDFF vs CAP for diagnosis of steatosis (grades 1-3 vs 0) with respect to findings from biopsy analysis.
Results
MRE detected any fibrosis (stage 1 or more) with an area under the receiver operating characteristic curve (AUROC) of 0.82 (95% confidence interval [CI], 0.74-0.91), which was significantly higher than that of TE (AUROC, 0.67; 95% CI, 0.56-0.78). MRI-PDFF detected any steatosis with an AUROC of 0.99 (95% CI, 0.98-1.00), which was significantly higher than that of CAP (AUROC, 0.85; 95% CI, 0.75-0.96). MRE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.89 (95% CI, 0.83-0.96), 0.87 (95% CI, 0.78-0.96), and 0.87 (95% CI, 0.71-1.00); TE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.86 (95% CI, 0.77-0.95), 0.80 (95% CI, 0.67-0.93), and 0.69 (95% CI, 0.45-0.94). MRI-PDFF identified steatosis of grades 2 or 3 with AUROC values of 0.90 (95% CI, 0.82-0.97) and 0.92 (95% CI, 0.84-0.99); CAP identified steatosis of grades 2 or 3 with AUROC values of 0.70 (95% CI, 0.58-0.82) and 0.73 (95% CI, 0.58-0.89).
Conclusions
In a prospective, cross-sectional study of more than 100 patients, we found MRE to be more accurate than TE in identification of liver fibrosis (stage 1 or more), using biopsy analysis as the standard. MRI-PDFF is more accurate than CAP in detecting all grades of steatosis in patients with NAFLD.
Nonalcoholic fatty liver disease (NAFLD) is increasingly emerging as the predominant cause of chronic liver disease around the world.1 In the United States, NAFLD is estimated to affect nearly 100 million adults, or one-third of the population, and its prevalence is predicted to rise along with rates of obesity, diabetes, and metabolic syndrome.2, 3 NAFLD ranges from simple benign hepatic steatosis or nonalcoholic fatty liver to severe hepatocellular inflammation known as nonalcoholic steatohepatitis.4, 5 This latter condition is estimated to affect 5% of the US population and carries a higher risk of progressing to cirrhosis and hepatocellular carcinoma.6, 7, 8 Although liver biopsy is the current gold standard for assessing NAFLD, its accuracy has been questioned because of sampling errors and variable intra- and inter-observer agreement.9, 10, 11 In addition, biopsy is invasive, which limits its use as a population screening tool. There is a need for accurate, noninvasive methods that can clinically assess NAFLD.
Liver fibrosis and steatosis are 2 features of NAFLD that have been investigated by noninvasive imaging tests to assess NAFLD. Transient elastography (TE; FibroScan, Echosens, Paris, France) is an ultrasound-based imaging technique that allows rapid, bedside measurements of tissue stiffness.12 TE-based liver stiffness measurements using the M probe have shown to correlate with stages of fibrosis, particularly in severe fibrosis and cirrhosis.13, 14, 15 Additionally, the controlled attenuation parameter (CAP) allows TE to simultaneously assess steatosis.16, 17, 18 An important limitation of TE is the high failure rates in obese patients with body mass index (BMI) >28 kg/m2, which limits reliable measurement of liver stiffness and steatosis in a significant portion of obese NAFLD patients.19, 20 However, the new XL probe equipped with CAP has been shown to reduce the failure rate for measuring fibrosis and steatosis in obese patients.21, 22
Magnetic resonance imaging (MRI)-based techniques, such as magnetic resonance elastography (MRE) and proton density fat fraction (PDFF) have been shown to accurately diagnose fibrosis and steatosis, respectively, in NAFLD patients.23, 24, 25, 26, 27, 28, 29 Although MRI-based techniques have been found to be accurate and effective in patients with obesity,30 they are more expensive and not widely available compared with TE.31 A recent Japanese study by Imajo etal32 directly compared and demonstrated that MRE and MRI-PDFF have higher accuracy than TE and CAP, respectively, for diagnosing fibrosis and steatosis in NAFLD patients. However, this study assessed TE using the M probe only. Therefore, TE using M or XL probe, when indicated, has not been compared with MRE. Furthermore, MRI-based techniques and TE have not yet been compared in a Western cohort of NAFLD patients who are likely to have higher BMI and may have other characteristics that can affect the diagnostic performance of TE and MRE.
Using a well-characterized, prospective cohort of American adults with biopsy-proven NAFLD, we compared the accuracy of TE vs MRE for diagnosing fibrosis, and CAP vs MRI-PDFF for diagnosing steatosis in NAFLD patients. We hypothesize that MRE is superior to TE for diagnosing earlyfibrosis, and that MRI-PDFF is superior to CAP for diagnosing steatosis in NAFLD patients.
Materials and Methods
Study Design
This was a prospective, cross-sectional study of patients with suspected NAFLD who underwent contemporaneous MRI and TE with a liver biopsy assessment. Between October 2011 and May 2016, one hundred and four adult patients with clinical indication for liver biopsies for suspected NAFLD were consecutively enrolled with written informed consent. After undergoing evaluation for other causes of hepatic steatosis and liver disease, patients were invited to undergo standardized history, physical and anthropometric examination, laboratory testing, MRI at the University of California at San Diego (UCSD) MR3T Research Laboratory, and TE at the UCSD NAFLD Research Center.4, 33, 34, 35, 36, 37 This study was Health Insurance Portability and Accountability Act of 1996-compliant and approved by the UCSD Institutional Review Board and the Clinical and Translational Research Institute.
Inclusion/Exclusion Criteria
We included patients ≥18 years old with suspected NAFLD patients who are willing and able to provide informed consent. Exclusion criteria were history of significant alcohol intake within 2 years of recruitment (≥14 drinks/wk for men or ≥7 drinks/wk for women); any evidence of secondary causes of hepatic steatosis, including nutritional, iatrogenic, or infectious etiology or human immunodeficiency virus infection; evidence of liver diseases other than NAFLD, which include viral hepatitis (screened by positive serum hepatitis B surface antigen and hepatitis C RNA assays), autoimmune hepatitis, genetic or acquired disorders such as hemochromatosis, Wilson's disease, glycogen storage disease, α-1 antitrypsin deficiency, and cholestatic or vascular liver disease; evidence of decompensated liver disease (defined as Child-Pugh score >7 points); active substance use; major systemic illnesses; contraindication(s) to MRI; pregnant or trying to become pregnant; or any other conditions believed by the principal investigator to affect patient's competence, compliance, or completion of the study.
Clinical Research Evaluation
All patients underwent a standardized clinical evaluation that included history, anthropometric examination, and biochemical tests at the UCSD NAFLD Research Center. Documented information from history and anthropometric examination included age, sex, height, weight, BMI, ethnic background, and vital signs. Alcohol intake history was assessed in prior clinical visits and reassessed at the research unit with the Alcohol Use Disorders Identification Test and the Skinner questionnaire. Other causes of liver diseases and secondary causes of hepatic steatosis, such as steatogenic medications, were ruled out systematically using history and biochemical tests. Biochemical tests included aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, α-glutamyl transpeptidase, total bilirubin, direct bilirubin, albumin, fasting glucose, hemoglobin A1c, insulin, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, platelet, prothrombin time, and international normalized ratio.
Histologic Evaluation
All patients underwent liver biopsy for assessment by an experienced liver pathologist who was blinded to the patient's clinical and radiologic data. Histologic scoring was done using the Nonalcoholic Steatohepatitis Clinical Research Network Histologic Scoring System.38 This scoring system is described further in the Supplementary Material.
Outcome Measures
The primary outcomes were fibrosis (stages 1-4 vs 0) and steatosis (grades 1-3 vs 0). Secondary outcomes included dichotomized stages of fibrosis (stages 2-4 [significant fibrosis] vs 0-1, stages 3-4 [advanced fibrosis] vs 0-2, and stage 4 [cirrhosis] vs stages 0-3), grades of steatosis (grades 2-3 vs 0-1, and grades 3 vs 0-2), and nonalcoholic steatohepatitis (NASH) vs no NASH.
Magnetic Resonance Imaging
MRI of the abdomen was performed at the UCSD MR3T Research Laboratory on a single 3T MR scanner (GE Signa EXCITE HDxt, GE Healthcare, Waukesha, WI). MRI-PDFF sequences were acquired according to methods published previously.28, 29, 39 Median time interval between MRI and biopsy was 42 days.
Magnetic Resonance Elastography
MRE was performed according to methods described previously25, 30, 40 on commercially available software and hardware (Resoundant, Inc, Rochester, MN) and is further described in the Supplementary Material.
Transient Elastography
TE was performed using the FibroScan 502 Touch model (MProbe, XL Probe; Echosens, Paris, France) by a trained technician blinded to clinical and histologic data, according to methods described previously.12, 22 Briefly, patients were asked to fast at least 3 hours before the examination. The procedure was performed in the supine position with the right arm fully adducted during a 10-second breath hold. Based on the manufacturer's recommendation, all patients were first scanned by applying the M probe (3.5 MHz) over the area of abdomen at the location of the right liver lobe. When indicated by the equipment upon initial assessment, patients were rescanned using the XL probe (2.5 MHz). A minimum of 10 measurements were made to obtain the median valid liver stiffness measurements (in kPa) and interquartile range. Technical failure was defined as no stiffness measurement obtained or unreliable measurements (defined as success rate <60% or interquartile range/median >30%).41 Simultaneous liver steatosis measurements were obtained using the CAP values in dB/m, colocalized to the valid liver stiffness measurements. All CAP data were collected prospectively. Median time interval between TE and biopsy was 107 days.
Statistical Analyses
All statistical analyses were performed using SAS, version 9.4 (SAS Institute, Cary, NC). Patients' demographic, biochemical, histologic, and imaging characteristics were summarized as mean and SD for continuous variables and numbers and percentages for categorical variables. A 2-tailed P value ≤ .05 was considered statistically significant.
Main analyses
Receiver operating characteristic curve analyses were used to compare the performances of MRE vs TE for diagnosing fibrosis (stages 1-4 vs 0), and MRI-PDFF vs CAP for diagnosing steatosis (grades 1-3 vs 0) with respect to biopsy. For each receiver operating characteristic analysis, the area under the receiver operating characteristic curve (AUROC), the optimal thresholds, and the following performance parameters were calculated: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The optimal threshold of each modality was determined using the Youden Index.42The Delong test was used to compare the AUROCs of MRE vs TE for diagnosing fibrosis, and CAP vs MRI-PDFF for diagnosing steatosis.43 Multivariable ROC analyses were performed to assess the effect of biopsy-to-imaging time interval and probe type on the AUROCs.
Secondary analyses
The following additional ROC curve analyses were performed: MRE vs TE for diagnosing other dichotomized stages of fibrosis (stages 2-4 vs 0-1; stages 3-4 vs 0-2, and stages 4 vs 0-3) and NASH vs no NASH; and MRI-PDFF vs CAP for diagnosing other dichotomized grades ofsteatosis (grades 2-3 vs 0-1, and grade 3 vs 0-2). The Kruskal-Wallis test was used to compare liver stiffness and steatosis measurements between groups at different stages of fibrosis and grades of steatosis, respectively.
Results
Baseline Characteristics
In this prospective study, 104 patients with liver biopsy, MRI, and TE were consecutively enrolled. Mean ± SD age and BMI were 50.8 ± 14.6 years and 30.4 ± 5.2 kg/m2, respectively. Baseline cohort characteristics are summarized in Table1. A total of 110 patients with biopsy-proven NAFLD were initially seen at the NAFLD Research Center, although 6 patients were excluded because TE was not performed. Of the 104 TE examinations, 7 (6.7%) resulted in technical failure.
Distribution of fibrosis stages and steatosis grades
There were 47, 24, 11, 13, and 8 patients with stages 0, 1, 2, 3, and 4 fibrosis, respectively; and 9, 49, 29, and 16 patients with grades 0, 1, 2, and 3 steatosis, respectively.
Comparison of magnetic resonance elastography and transient elastography for diagnosing fibrosis
MRE had an AUROC of 0.82 (95% confidence interval [CI], 0.74-0.91) for diagnosing fibrosis stages 1-4 vs 0. Using a threshold of 2.65 kPa, MRE had a sensitivity of 76.5%, specificity of 79.1%, PPV of 81.3%, and NPV of 73.9% (Figure1). TE had an AUROC of 0.67 (95% CI, 0.56-0.78) for diagnosing fibrosis. Using a threshold of 6.10 kPa, TE had a sensitivity of 66.7%, specificity of 65.1%, PPV of 69.4%, and NPV of 62.2%. Direct comparison using the Delong test showed that MRE is significantly more accurate than TE (P= .0116) for diagnosing any fibrosis (Table2).
Comparison of MRE and TE for diagnosing other dichotomized stages of fibrosis: The AUROCs of MRE and TE for diagnosing other dichotomized stages of fibrosis are summarized in Table2. For diagnosing stages 2-4 vs 0-1, stages 3-4 vs 0-2, and stages 4 vs 0-3 fibrosis, respectively, MRE had AUROCs of 0.89 (95% CI, 0.83-0.96), 0.87 (95% CI, 0.78-0.96), and 0.87 (95% CI, 0.71-1.00), and TE had AUROCs of 0.86 (95% CI, 0.77-0.95), 0.80 (95% CI, 0.67-0.93), and 0.69 (95% CI, 0.45-0.94). Direct comparisons showed that MRE is more accurate than TE for diagnosing any fibrosis (stages 1-4 vs 0), but no significant difference existed between MRE and TE for diagnosing other dichotomized stages of fibrosis.
The mean ± SD liver stiffness for stages 0, 1, 2, 3, and 4 fibrosis measured by MRE was 2.37 ± 0.38, 2.82 ± 0.65, 3.49 ± 0.71, 4.51 ± 1.74, and 5.16 ± 1.62 kPa, respectively. Similarly, the mean ± SD liver stiffness for stage 0, stages 1, 2, 3, and 4 fibrosis by TE was 6.89 ± 10.37, 8.07 ± 13.48, 9.89 ± 2.67, 11.3 ± 4.93, and 10.39 ± 4.95, respectively.
Comparison of magnetic resonance elastography and transient elastography for diagnosing histologic nonalcoholic steatohepatitis
For diagnosing NASH, MRE had AUROC of 0.70 (95% CI, 0.57-0.82), which was significantly higher than TE AUROC (P= .0011) of 0.35 (95% CI, 0.22-0.49).
Comparison of magnetic resonance imaging proton density fat fraction and controlled attenuation parameter for diagnosing steatosis
MRI-PDFF had an AUROC of 0.99 (95% CI, 0.98-1.00) for diagnosing any steatosis (grades 1-3 vs 0). Using a threshold of 3.71%, MRI-PDFF had a sensitivity of 95.8%, specificity of 100%, PPV of 100%, and NPV of 70.0% for diagnosing steatosis (Figure2). CAP had an AUROC of 0.85 (95% CI, 0.75-0.96). Using a threshold of 261 dB/m, CAP had a sensitivity of 71.8%, specificity of 85.7%, PPV of 98.1%, and NPV of 23.1%. Direct comparison showed that MRI-PDFF is more accurate than CAP for diagnosing (P= .0091) any steatosis (Table3).
Comparison of magnetic resonance imaging proton density fat fraction and controlled attenuation parameter for diagnosing other dichotomized grades of steatosis
The AUROCs of MRI-PDFF and CAP for diagnosing other dichotomized grades of steatosis are summarized in Table3. For diagnosing grades 2-3 vs 0-1 and grades 3-4 vs 0-2 steatosis, respectively, MRI-PDFF had AUROCs of 0.90 (95% CI, 0.82-0.97) and 0.92 (95% CI, 0.84-0.99), and CAP had AUROCs of 0.70 (95% CI, 0.58-0.82) and 0.73 (95% CI, 0.58-0.89). Direct comparison showed that MRI-PDFF was more accurate than CAP at all dichotomization cutoff points for diagnosing steatosis. Distributions of liver stiffness measurements by MRE and TE are illustrated in Figure3A. Distributions of liver steatosis measurements by MRI-PDFF and CAP are illustrated in Figure3B.
Multivariable-adjusted receiver operating characteristic analyses adjusted for biopsy-to-imaging time interval and probe type
The adjusted ROC analyses are summarized in Supplementary Tables1 and 2. There was no significant difference in the performances of MRE, TE, MRI-PDFF, or CAP between unadjusted and adjusted models, when either biopsy-to-imaging time interval or type of probe was included as covariates.
Discussion
Summary of Main Findings
Using a prospective, well-characterized, US-based cohort of patients, this study demonstrates that MRE is more accurate than TE for diagnosing liver fibrosis in patients with NAFLD. The key novelty of this study is that this is first study using the XL probe to perform head-to-head comparison between MRE vs TE, and MRI-PDFF vs CAP, providing estimates of differences in diagnostic accuracy of these modalities in a Western NAFLD population that has a higher BMI than Asian NAFLD population so these results are more generalizable to Western cohorts. Furthermore,this study showed that MRI-PDFF is significantly more accurate than CAP for diagnosing all dichotomized grades ofhepatic steatosis. These results may have important implications in developing an optimal clinical approach fornoninvasive assessment of NAFLD. Although cost-effectiveness studies are needed to determine the optimal approach, we propose that an MRI-based approach may be preferable to TE when accurate steatosis and fibrosis quantification is needed, such as in the setting of a clinical trial, because MR-based methods have higher precision and accuracy than TE-based assessment. TE may be preferable in routine clinical assessment at the level of population for screening out advanced fibrosis among low-risk patient populations. However, additional studies are needed to draw more definite conclusions.
In the context of published literature
This is the first prospective study to directly compare the accuracy of MRE and TE for diagnosing fibrosis, and MRI-PDFF vs CAP for diagnosing steatosis in a well-characterized cohort of American adults with biopsy-proven NAFLD. Both MRE and TE were not adequate for diagnosing NASH. Our study is consistent with prior studies showing MRI to have high diagnostic accuracy for fibrosis and steatosis in NAFLD patients.23, 24, 25, 28, 29 Our study is also consistent with prior studies showing TE to have high negative predictive value for diagnosing significant fibrosis (stages 2-4), severe fibrosis (stages 3-4), and cirrhosis,14, 15 and CAP to be accurate for diagnosing any steatosis, but not at higher dichotomized grades of steatosis.17, 18
A recent seminal study by Imajo etal32 has shown that MRE is more accurate than TE for diagnosing significant fibrosis (stages 2-4 vs 0-1) and cirrhosis in Japanese NAFLD patients. In comparison, our study showed that MRE is more accurate than TE for diagnosing any fibrosis (stages 1-4 vs 0), but not cirrhosis (P= .0546) Although Imajo etal assessed TE using the M probe only, we also used the XL probe when indicated during our examination (n= 53). Our cohort's demographic characteristics, such as race and higher BMI (30.5 ± 5.2 kg/m2) may have reflected a more accurate assessment of the diagnostic performances and cutoffs of MRI and TE in a Western population. Future studies with a larger cohort of patients may be needed to determine the optimal cutoff points for MRI-PDFF vs CAP for the grade of steatosis in NAFLD as well as MRE vs TE for the stage of fibrosis in NAFLD, which may be different for Western NAFLD population vs Asian NAFLD population.
Liver fibrosis and steatosis are clinically important features of NAFLD that have been investigated by noninvasive tests, such as MRI and TE. Steatosis alone is known to progress to NASH and fibrosis.8 In addition, any fibrosis, even in the absence of severe fibrosis (stages 3-4), compared with no fibrosis was shown to be associated with increased mortality or liver transplantation rates in NAFLD patients.44 Therefore, early diagnosis and screening of fibrosis and steatosis before progression to severe fibrosis and/or NASH may benefit NAFLD patients. We acknowledge that liver histology, liver stiffness by TE, liver stiffness by MRE, ultrasound attenuation for CAP assessment, and steatosis quantification by MRI-PDFF all assess different properties using different physical properties. Therefore, although some of these would be co-linear with each other, they are not likely to be identical, as each assesses different properties of liver tissue. In addition, the prognostic significance of changes in liver fat have not yet been assessed in long-term clinical trials, reduction in liver fat content by MRI-PDFF may have utility in short-term trials, as shown previously.34, 45, 46 Our study shows that MRI-based techniques are superior to TE for detecting any fibrosis and steatosis in NAFLD patients who may be at increased risk for mortality and other poor prognostic outcomes. Other advantages of MRI-based techniques over TE include larger area of the liver measured, which may reduce sampling variability secondary to heterogeneity of fibrosis,9, 11 and the utility of MRI-PDFF for assessing longitudinal changes in steatosis.47 Although TE has excellent inter- and intra-operator reproducibility48 and is accurate for diagnosing cirrhosis,12 its applicability is limited by high failure rates in patients with narrow intercostal space and ascites,12 interference of liver stiffness measurements by extrahepatic cholestasis and acute liver injury,49, 50 and reduced reproducibility in early stages of fibrosis and in the presence of steatosis.48, 51
Strengths and Limitations
The strength of this study included use of a well-characterized, prospective cohort of NAFLD patients undergoing liver biopsy for clinical indication. Liver biopsy, used as the reference standard for imaging, was scored using the NASH Clinical Research Network Histologic Scoring System, which is well-validated for assessing NAFLD patients. This study was performed by experienced investigators at a dedicated research center that is specialized for both clinical and radiologic research in NAFLD, and patients were carefully evaluated to exclude other causes of liver disease before inclusion in the study.
However, this study also had the following limitations. The cross-sectional design of the study did not allow the assessment of MRE and TE for monitoring longitudinal changes in fibrosis. Because this was a single-center study in a highly specialized setting, the generalizability of its findings in other clinical settings is unknown. Median time interval between TE and biopsy was 107 days. A recent meta-analysis of paired liver biopsy studies has shown that the rate of fibrosis progression is slow, with a mean progression of one stage to take 14.3 years in patients with nonalcoholic fatty liver and 7.1 years in patients with NASH.6 Therefore, our time interval is reasonable, as fibrosis stage is unlikely to change within a year. Furthermore, our analyses showed that the biopsy-to-imaging time interval did not affect the diagnostic accuracy of MRI and TE. Nevertheless, rapid changes in steatosis are possible, and ideally biopsy and imaging should be performed contemporaneously within 1 week, if feasible. MRI-based techniques, including MRE and MRI-PDFF, are often expensive, although at our center the cost of MRE is lower than that of biopsy without the associated morbidity. Although TE is more widely available in some parts of the world, MRI techniques are more widely deployed in the United States, therefore, MRE can also be made available on commercially available MRI platforms throughout the United States. Although TE might be more useful for widespread screening, MRE can play a role in clinical trial assessments that require higher accuracy and precision. Further studies are needed to evaluate the cost-effectiveness of MRI over TE for diagnosing NAFLD-related fibrosis and steatosis before implementing these competing noninvasive approaches in routine clinical practice.
Implication for Future Research
Using prospective, head-to-head comparisons, we found that MRI-based MRE and MRI-PDFF are significantly more accurate than ultrasound-based TE and CAP, respectively, for diagnosing fibrosis and steatosis in an American cohort of patients with biopsy-proven NAFLD. MRI-based techniques may be preferable to TE for accurate noninvasive assessment of NAFLD. Future studies are necessary to assess the clinical utility of MRI and TE for diagnosing fibrosis and steatosis in a multicenter, longitudinal design, both in observational and intervention studies. The cost-effectiveness of utilizing MRE vs TE and/or biopsy must also be evaluated to develop optimal diagnostic strategies for diagnosing NAFLD-associated fibrosis and steatosis.
Supplementary Methods
Histologic Assessment
Hepatic fibrosis was scored from 0 to 4 (0, 1, 2, 3, 4), steatosis and lobular inflammation were scored from 0 to 3 (0, 1, 2, 3), and hepatocellular ballooning was scored from 0 to 2 (0, 1, 2). The sum of these scores, known as the NAFLD Activity Score was calculated. NASH was scored on a 3-point scale (no NASH, borderline NASH, or definite NASH). Patients with borderline or definite NASH were considered as having NASH in this study.
Magnetic Resonance Elastography
A standard 60-Hz shear-wave was generated by an acoustic passive driver attached to the body wall anterior to the liver and coupled with an acoustic active driver outside the MR examination room. A 2-dimensional motion-sensitized gradient-recalled echo MRE pulse sequence synchronized to the shear wave frequency was acquired to obtain 4 noncontiguous axial slices (10-mm thickness, 10-mm inter-slice gap), each during a 16-second breath hold, through the widest transverse section of the liver with short recovery times in between. The acquisition parameters were as follows: repetition time, 50 milliseconds; echo time, 20.2 milliseconds; flip angle, 30 degrees; matrix, 256x 64; field of view, 48x 48 cm; one-signal average; receiver bandwidth ± 33 kHz; and parallel imaging accelerating factor, 2. The total acquisition time was approximately 2 minutes.
The wave images from each slice location were automatically processed on the scanner computer using inversion algorithm to generate axial liver stiffness maps called elastograms. The elastograms were transferred and analyzed offline by a trained image analyst (at least 6 months of experience with MRE analysis) blinded to clinical and histologic data. While avoiding liver edges, large blood vessels, and artifacts, the image analyst drew regions of interests on the elastograms using a custom software package in parts of the liver where wave propagation was shown clearly on the wave images. The mean per-pixel liver stiffness values across regions of interests at the 4 slices were calculated and automatically recorded in an electronic spreadsheet.
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