We read with great interest the study by Di Costanzo et al. regarding the clinical trade-off between cardiovascular protection and hepatic risk in individuals carrying APOB loss of function variants 1. The authors provide valuable epidemiological evidence confirming that genetic impairment of hepatic lipoprotein export reduces circulating lipids at the cost of increased liver fat. However, several issues warrant further discussion. Our primary concern relates to the phenotypic precision of the liver disease endpoints used in the broader UK Biobank cohort. The study relies heavily on serum aminotransferases and administrative codes which are known to lack sensitivity for detecting metabolic dysfunction associated steatotic liver disease. Data from the UK Biobank imaging sub-study indicate that a substantial proportion of individuals with magnetic resonance confirmed steatosis exhibit liver enzyme levels strictly within the normal reference range 2. By utilising these insensitive surrogates the analysis may conflate benign retention steatosis with progressive steatohepatitis. We suggest that a focused analysis restricted to the magnetic resonance imaging sub-study would offer the granular data necessary to distinguish simple fat accumulation from clinically significant pathology. Furthermore, the net clinical benefit analysis presents a challenge regarding endpoint equivalence. The methodology subtracts the incidence of chronic liver disease events from prevented atherosclerotic cardiovascular events, which implicitly treats these outcomes as having equal clinical weight. This approach is problematic because the immediate mortality and morbidity associated with an acute myocardial infarction significantly exceed those of an early diagnosis of fatty liver disease 3. A more robust assessment would incorporate quality of life weighting or disability adjusted life years to accurately reflect the disparity between preventing a fatal cardiac event and incurring a chronic hepatic condition. Finally, the interaction between APOB variants and the PNPLA3 I148M risk allele warrants deeper investigation beyond simple stratification. The PNPLA3 variant promotes lipid retention through a distinct mechanism involving the sequestration of polyunsaturated fatty acids on lipid droplets 4. The combination of an APOB export defect and a PNPLA3 remodelling defect likely creates a synergistic double hit that drives the majority of the observed liver risk 5. Understanding this epistatic interaction is crucial for precision medicine as the hepatic risk may be minimal in the absence of the PNPLA3 risk allele. Manuscript draft, manuscript review and editing: Pingfeng Wang, Xiaoyu Chen and Yanjin Song. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Di Costanzo et al. papers. To view this article, visit https://doi.org/10.1111/liv.70515. The authors have nothing to report.
Wang et al. (Tue,) studied this question.