Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials

Davison, Beth A.; Harrison, Stephen A.; Cotter, Gad; Alkhouri, Naim; Sanyal, Arun J.; Edwards, Christopher; Colca, Jerry R.; Iwashita, Julie; Koch, Gary G.; Dittrich, Howard C.

doi:10.1016/j.jhep.2020.06.025

Cited by 285 publications

(293 citation statements)

References 44 publications

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“…In addition, compared to other histological features, such as fibrosis, the histological diagnosis of NASH exhibits a large inter-and intra-observer variability and sampling error, which is reflected by the widely ranging prevalence of NASH, from 1.4% to 20% of liver biopsies [42]. This lack of reliability in the assessment of NASH may also affect NASH trials, by introducing patients who do not meet entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects [43]. For instance, in the sole Phase 3 clinical trial for NAFLD to date that showed significant results, obeticholic acid failed to demonstrate a significant impact on NASH resolution, though it had a significant effect on fibrosis [44,45].…”

Section: And Beyondmentioning

confidence: 99%

History of Nonalcoholic Fatty Liver Disease

Lonardo¹,

Leoni

Alswat

et al. 2020

IJMS

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Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig’s seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of “NAFLD as a manifestation of the Metabolic Syndrome”, to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.

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Section: And Beyondmentioning

confidence: 99%

History of Nonalcoholic Fatty Liver Disease

Lonardo¹,

Leoni

Alswat

et al. 2020

IJMS

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“…We read with great interest the paper published by Davison et al 1 In this study, the authors demonstrate that the low reproducibility of the non-alcoholic steatohepatitis (NASH) CRN scoring system affects the power of clinical trials in nonalcoholic fatty liver disease (NAFLD). Specifically, the lack of consistency has a significant impact on several fundamental aspects of the conduct of trials in NAFLD, for instance both inclusion criteria and histological endpoints.…”

Section: Nafld: Time To Apply Quantitation In Liver Biopsies As Endpomentioning

confidence: 99%

“…In the EMMINENCE study, the 3 expert pathologists agreed only on one-third of the screened patients meeting histological criteria. 1 From an industry perspective, the large number of ineffective biopsies adds significantly to the cost and duration of clinical trials, as well as impacting upon power calculations and consequently sample sizes. Furthermore, from a clinical standpoint, there is the potential for patients not suitable for treatment to be included in studies, with this affecting the interpretation of the drug effect on the disease.…”

Section: Nafld: Time To Apply Quantitation In Liver Biopsies As Endpomentioning

confidence: 99%

“…In the EMMINENCE study, the magnitude of effect of the drug on histology was proportional to the degree of agreement between pathologists. 1 It should be noted that differences in semi-quantitative scores do not necessarily correspond to quantitative changes of histological features. 4 Specifically, we have previously demonstrated that quantitation is more sensitive than the CRN scoring system in showing changes in a subgroup of liver biopsies.…”

Section: Nafld: Time To Apply Quantitation In Liver Biopsies As Endpomentioning

confidence: 99%

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NAFLD: Time to apply quantitation in liver biopsies as endpoints in clinical trials

Forlano

Mullish

Maurice

et al. 2021

Journal of Hepatology

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“…With great interest we read the manuscript by Beth Davidson and colleagues that highlights variability and reduced reliability of liver histology in a phase IIb clinical trial in non-alcoholic steatohepatitis (NASH). 1 The published analysis provides data on the blinded, unstructured reassessment of liver histology and demonstrates a relevant degree of disagreement. The study highlights a central, yet vulnerable aspect that applies to most clinical trials currently conducted in NASH: the assessment of liver histology.…”

Section: To the Editormentioning

confidence: 99%