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• W2150151840 abstract "Potential conflict of interest: Dr. Caldwell consults for Wellstat and received grants from Gilead, Immuron, and NGM. To the Editor: Histopathology serves as the cornerstone for translating disease pathophysiology. We were excited to see several articles in Hepatology involving hepatocellular ballooning, Sonic Hedgehog (SHH) expression, PNPLA3, and TM6 genetic variation, all of which seem to converge on the fat droplet.1 These findings support the previously reported association between fat droplet accumulation, hepatocyte enlargement, loss of keratin‐8,18 staining, and the presence of Mallory‐Denk bodies.7 We postulated that oxidative injury to fat droplets’ phospholipid membrane impairs function of the proteins that govern insulin‐mediated access to the droplet, disrupts directional droplet trafficking along the cytoskeleton, and impedes small droplets’ coalescence into stable macrovesicular droplets.9 We speculated that impaired droplet coalescence resulting from oxidative injury leads to “derelict” droplets prone ultimately to rancidification—a fitting component of the “undead” ballooned hepatocytes.10 The proposed TM6‐mediated reciprocal relationship between nonalcoholic steatohepatitis (NASH) and systemic dyslipidemia hearkens further to earlier fat droplet studies in alcoholic steatosis by Cairns et al.11 In contrast, we were disappointed to note perpetuation of misconceptions from the PIVENS trial in two of the articles, which dismissed pioglitazone as ineffective in NASH.1 The inconsistency in assessing ballooning by conventional hematoxylin and eosin staining and its marked effect on nonalcoholic fatty liver disease activity score (NAS) negatively affect the utility of a 2‐point NAS reduction as an outcome.13 In PIVENS, post‐hoc analysis of biopsies resulted in approximately 20% of all subjects not meeting entry criteria for ballooning.13 Based on the predetermined primary outcome of 2‐point NAS reduction, which was developed in a consensus conference and has never been validated,16 vitamin E was superior to pioglitazone. However, using the more reliable and meaningful histological endpoint, absence of definite NASH,17 pioglitazone was approximately twice as effective as vitamin E. The 2‐point NAS reduction as the primary outcome in NASH perpetuates a problematic, arbitrary endpoint. Clearly, ballooning is a critical pathophysiological finding and likely occurs across a spectrum in NASH. Future studies should consider how to better assess this key parameter and determine the most reproducible, clinically useful outcome related to disease pathophysiology." @default.
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• W2150151840 date "2015-10-01" @default.
• W2150151840 modified "2023-10-18" @default.
• W2150151840 title "The fat droplet in hepatocellular ballooning and implications for scoring nonalcoholic steatohepatitis therapeutic response" @default.
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• W2150151840 doi "https://doi.org/10.1002/hep.28009" @default.
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