Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease

Middleton, Michael S.; Natta, Mark L. Van; Heba, Elhamy; Alazraki, Adina; Trout, Andrew T.; Masand, Prakash; Brunt, Elizabeth M.; Kleiner, David E.; Doo, Edward; Tonascia, James; Lavine, Joel E.; Shen, Wei; Hamilton, Gavin; Schwimmer, Jeffrey B.; Sirlin, Claude B.

doi:10.1002/hep.29596

Cited by 114 publications

(93 citation statements)

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“…In the phase 2 trial of OCA, an absolute 6% change in PDFF correlated with change in histological steatosis grade after treatment . Similarly, in a pediatric treatment trial, changes in PDFF correlated with histological changes . A treatment trial with ezetimibe showed that histological responders had a significant decrease in PDFF, and a secondary analysis of these data showed that an absolute reduction in PDFF by 4.1% or a relative reduction in PDFF by 29.3% (±29% [SD]) correlated with a ≥2‐point reduction in NAS, although the relatively small sample size (N = 10) and variability in PDFF among patients highlight the need for further validation of this threshold value .…”

Section: Measures Of Nash Severity and Changes In Nash Severitymentioning

confidence: 95%

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum

et al. 2019

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on behalf of the Liver Forum Case Definitions Working GroupIdentifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood-based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials. (Hepatology 2019;70:1841-1855).

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Section: Measures Of Nash Severity and Changes In Nash Severitymentioning

confidence: 95%

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum

et al. 2019

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“…However, it is technically demanding, time‐consuming, and potentially erroneous, as it typically samples only a small portion of the liver compared with the latter. Given this, CSE‐MRI that rapidly covers the entire liver with a refined pulse sequence corrects for T 1 bias, T 2 * decay, and spectral complexity of fat is gaining popularity as the method of choice for quantifying hepatic steatosis in response to pharmaceutical treatment in clinical trials …”

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confidence: 99%

“…Given this, CSE-MRI that rapidly covers the entire liver with a refined pulse sequence corrects for T 1 bias, 10 T 2 * decay, 11 and spectral complexity of fat 12 is gaining popularity as the method of choice for quantifying hepatic steatosis in response to pharmaceutical treatment in clinical trials. [13][14][15][16][17] For a new metric to be adopted as a robust quantitative imaging biomarker (QIB), several key performance components need to be assessed beforehand, as proposed by the Radiological Society of North America Quantitative Imaging biomarker Alliance (QIBA): linearity, bias, and precision. 18,19 Linearity is the ability of QIB to deliver measured values that are directly proportional to true values, while bias is the difference between the mean of QIB measurements and true values.…”

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confidence: 99%

Accuracy and precision of proton density fat fraction measurement across field strengths and scan intervals: A phantom and human study

Kim

Cho

Kim

et al. 2018

Magnetic Resonance Imaging

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Background Complex‐based chemical shift imaging‐based magnetic resonance imaging (CSE‐MRI) is emerging as a preferred method for noninvasively quantifying proton density fat fraction (PDFF), a promising quantitative imaging biomarker (QIB) for longitudinal hepatic steatosis measurement. Purpose To determine linearity, bias, repeatability, and reproducibility of the PDFF measurement using CSE‐MRI (CSE‐PDFF) across scan intervals, MR field strengths, and readers in phantom and nonalcoholic fatty liver disease (NAFLD) patients. Study Type Institutional Review Board (IRB)‐approved prospective. Subjects Fat‐water phantom and 20 adult patients. Field Strength/Sequence 1.5 T and 3.0 T MR systems and a commercially available CSE‐MRI sequence (IDEAL‐IQ). Assessment Two independent readers measured CSE‐PDFF of fat‐water phantom and NAFLD patients across two field strengths and scan intervals (same‐day and 2‐week) each and in a combination of both. MR spectroscopy‐based PDFF (MRS‐PDFF) was used as the reference standard for phantom PDFF. Statistical Tests Linearity and bias of measurement were evaluated by linear regression analysis and Bland–Altman plots, respectively. Repeatability and reproducibility were assessed by coefficient of variance and repeatability / reproducibility coefficients (RC). The intraclass correlation coefficient was used to validate intra‐ and interobserver agreements. Results CSE‐PDFF showed high linearity and small bias (–0.6–0.4 PDFF%) with 95% limits of agreement within ±2.9 PDFF% across field strengths, 2‐week interscan period, and readers in the clinical scans. CSE‐PDFF was highly repeatable and reproducible both in phantom and clinical scans, with the largest observed RC across field strengths and 2‐week interscan period being 3 PDFF%. Data Conclusion CSE‐PDFF is a robust QIB with high linearity, small bias, and excellent repeatability/reproducibility. A change of more than 3 PDFF% across field strengths within 2 weeks of scan interval likely reflects a true change, which is well within the clinically acceptable range. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:305–314.

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“…Several studies have validated the use of MRI‐PDFF to quantify hepatic fat against both histology‐determined steatosis grade and MRI spectroscopy fat quantification . A recent study assessed the performance of MRI‐PDFF in 110 children with biopsy‐proven NASH and demonstrated excellent accuracy in classifying mild steatosis versus moderate/severe steatosis with an area under the receiving operator characteristic curve of 0.87 …”

Section: Differences Between Pediatric and Adult Nafldmentioning

confidence: 99%

“…(27)(28)(29)(30) A recent study assessed the performance of MRI-PDFF in 110 children with biopsy-proven NASH and demonstrated excellent accuracy in classifying mild steatosis versus moderate/ severe steatosis with an area under the receiving operator characteristic curve of 0.87. (31)…”

Section: Noninvasive Diagnostic Testsmentioning

confidence: 99%

Designing Clinical Trials in Pediatric Nonalcoholic Steatohepatitis: Tips for Patient Selection and Appropriate Endpoints

2019

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Nonalcoholic fatty liver disease (NAFLD) is common in children and may progress to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and even cirrhosis in childhood or early adulthood, indicating the need for pharmacologic treatment in this age group. Multiple trials are evaluating different therapeutic targets for NASH with fibrosis in adults, and the U.S. Food and Drug Administration has recently provided clear guidance to the pharmaceutical industry on developing drugs for the treatment of noncirrhotic NASH with liver fibrosis. Pediatric NAFLD has several unique aspects that distinguish it from the adult disease in terms of histology, our understanding of the natural history, and the utility of noninvasive tests. These differences have the potential to impact the design of clinical trials to test different drugs in the pediatric population. The aim of this article is to provide a review of common misconceptions regarding pediatric NAFLD and key differences from adult NAFLD. We have provided our recommendations on the design of early proof‐of‐concept and late phase 2 trials based on lessons learned from previous clinical trials. We believe that clinical drug development for children with NAFLD should happen in parallel with ongoing adult trials.

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Diagnostic accuracy of magnetic resonance imaging hepatic proton density fat fraction in pediatric nonalcoholic fatty liver disease

Abstract: MRI-estimated PDFF has high diagnostic accuracy to both classify and predict histological steatosis grade and change in histological steatosis grade in children with NAFLD. (Hepatology 2018;67:858-872).

Cited by 114 publications

References 46 publications

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum

Accuracy and precision of proton density fat fraction measurement across field strengths and scan intervals: A phantom and human study

Designing Clinical Trials in Pediatric Nonalcoholic Steatohepatitis: Tips for Patient Selection and Appropriate Endpoints

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