MRI‐Proton Density Fat Fraction Treatment Response Criteria in Nonalcoholic Steatohepatitis
Open accessAbstract
NASH is one of leading causes of chronic liver disease in the United States.(1) NASH can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma and has become one of the leading indications for liver transplant in the United States.(2) Reversal of NASH and improvement of NASH-related fibrosis is a major unmet need in the field of liver disease.Several therapies have shown promise in the treatment of NASH-related fibrosis, but there are no US Food and Drug Administration (FDA)-approved or European Medicines Agency (EMA)-approved therapies.Over the past 10 years, there has been a tremendous increase in the number of agents being evaluated for treatment of NASH-related fibrosis.Both the FDA and EMA have provided guidance regarding regulatory approval for drugs used in the treatment of NASH-related fibrosis.The acceptable endpoints for full approval include progression to cirrhosis, clinical hepatic decompensation, and a MELD score ≥15.However, because of the long natural history of NASH-related fibrosis, a subpart H pathway is provided to show improvement in liver histology as a surrogate endpoint for interim approval while data are being collected for long-term clinical outcomes.These histologic endpoints include ≥1 stage improvement in fibrosis without worsening of NASH and/or resolution of NASH without worsening of fibrosis.Histologic endpoints, although useful, pose significant limitations to clinical drug development in NASH.These limitations include the invasive nature of the liver biopsy assessment, subjective assessment of histology, low intrareader and inter-rater reliability, lack of precision and reproducibility, and long duration required to show a treatment benefit.Therefore, there is a need for a precise, reproducible, accurate biomarker for treatment response, especially in early Phase 1 and 2A trials in which histologic response assessment is impractical and may increase the risk of type 2 errors, i.e., declaring a therapy to be ineffective although it may improve NASH-related fibrosis in a larger and longer trial.(3) Over the last 10 years, many noninvasive tests, both serum and imaging-based biomarkers, have been proposed to assess treatment response in NASH.(4) Among the cadre of these noninvasive biomarkers, MRI-proton density fat fraction (MRI-PDFF) is one of the leading imaging-based biomarkers of assessing antisteatotic benefits of a drug therapy in NASH.(5)
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Non-invasive MASLD assessment by imaging indicated reduction of liver lipid content with tirzepatide treatment.
“Moreover, non-invasive MASLD assessment by imaging methods indicated a reduction of liver lipid content with tirzepatide treatment [131] (Table 1).”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [131]
In the main text (page unavailable), the paper describes MRI-PDFF as a noninvasive imaging method for quantifying liver fat and assessing treatment response in NASH. It does not report an imaging-measured reduction in liver fat with tirzepatide; searches for tirzepatide returned no such passage. (LLM, conf=0.84)
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Cites
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“(1) NASH can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma and has become one of the leading indications for liver transplant in the United States.”
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“(3) Over the last 10 years, many noninvasive tests, both serum and imaging-based biomarkers, have been proposed to assess treatment response in NASH.”
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“(1) NASH can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma and has become one of the leading indications for liver transplant in the United States.”
BackgroundNoninvasive, Quantitative Assessment of Liver Fat by MRI‐PDFF as an Endpoint in NASH Trials
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“, declaring a therapy to be ineffective although it may improve NASH-related fibrosis in a larger and longer trial.(3) Over the last 10 years, many noninvasive tests, both serum and imaging-based biomarkers, have been proposed to assess treatment response in NASH.”
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“(3) Over the last 10 years, many noninvasive tests, both serum and imaging-based biomarkers, have been proposed to assess treatment response in NASH.”
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“In subsequent multicenter studies with diverse therapies such as selonsertib (ASK-1 inhibitor) and obeticholic acid (farnesoid X receptor agonist), these data were then validated.(7,8) The optimal cut-point that was associated with histologic response was noted to be ≥30% relative reduction in MRI-PDFF.”
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“In a seminal single center study, it was noted that a significant reduction in liver fat by MRI-PDFF is associated with a higher odds of ≥2 point improvement in NAFLD activity score (NAS).(6) NAS ranges from 0 to 8 and is a summary score including steatosis ranging from 0 to 3, lobular inflammation 0 to 2, and balloon…”
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“(7,8) The optimal cut-point that was associated with histologic response was noted to be ≥30% relative reduction in MRI-PDFF.”
BackgroundMethodInfluentialSelf-citation
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Research works printed but not linked: 1
- [8]Loomba R, Neuschwander‐Tetri BA, Sanyal A, Chalasani N, Diehl AM, Terrault N, et al. Multicenter validation of association between decline in MRI‐PDFF and histologic response in nonalcoholic steatohepatitis. Hepatology 2020. 10.1002/hep.31121. [Epub ahead of print] PMC8055244 31965579 · DOI
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Sorted by citations
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“…thresholds as it has been established in the literature that a ≥30% relative reduction in MRI-PDFF is associated with histologic response (categorized as a responder) and that a ≥50% relative reduction in MRI-PDFF evokes a substantially higher histologic response (defined as a super responder) 48 .”
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“Analysis of a trial of ezetimibe in NASH showed that PDFF could distinguish histological responders from non-responders (32), which was later characterized as a relative reduction of ~30% liver fat corresponding to a two-point change in NAS (33, 34).”
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“The measurement of liver fat content via magnetic resonance imaging has been proposed and is now used in some early-phase phase NASH clinical trials [94,95].”
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“In the field of metabolic dysfunction-associated steatohepatitis (MASH), MRI is a preferred clinical trial tool that can non-invasively measure liver fat (e.g., via PDFF) and fibrosis (e.g., via MRE) [78].”
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- Authors
- Loomba, R.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Loomba, Rohit
- ORCID
- Loomba, Rohit
- Venue
- Hepatology
- Published
- 2021-03
- Volume
- 73
- Issue
- 3
- Pages
- 881-883
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC8221026
- OpenAlex
- W3103169657
- Cited by
- 36
- References
- 9
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 9
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH-18)
- National Institutes of Health (UL1TR001442)
- National Institute on Alcohol Abuse and Alcoholism (U01AA029019)
- National Heart, Lung, and Blood Institute (P01HL147835)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124318, R01DK121378, R01DK106419, P30DK120515, U01DK061734)
- National Institute of Environmental Health Sciences (P42ES010337)
- National Center for Advancing Translational Sciences
- DOD Peer Reviewed Cancer Research Program (W81XWH‐18‐2‐0026)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- nonalcoholic steatohepatitis, proton density fat fraction, treatment response criteria, non-invasive biomarkers, surrogate endpoints, liver histopathology, drug development
- MeSH terms
- Adipose Tissue, Clinical Trials as Topic, Humans, Liver, Magnetic Resonance Imaging, Protons, Biomarkers, Treatment Outcome, Non-alcoholic Fatty Liver Disease
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