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MicroRNAs (miRNAs) are short non-coding RNA species that play key roles in post-transcriptional regulation of gene expression. MiRNAs also serve as a promising source of early biomarkers for different environmental exposures and health effects, although there is limited information linking miRNA changes to specific target pathways. In this study, we measured liver miRNAs in male B6C3F1 mice exposed to a known chemical activator of the peroxisome proliferator-activated receptor alpha (PPARα) pathway, di(2-ethylhexyl) phthalate (DEHP), for 7 and 28 days at concentrations of 0, 750, 1500, 3000, or 6000 ppm in feed. At the highest dose tested, DEHP altered 61 miRNAs after 7 days and 171 miRNAs after 28 days of exposure, with 48 overlapping miRNAs between timepoints. Analysis of these 48 common miRNAs indicated enrichment in PPARα–related targets and other pathways related to liver injury and cancer. Four of the 10 miRNAs exhibiting a clear dose trend were linked to the PPARα pathway: mmu-miRs-125a-5p, -182−5p, -20a−5p, and -378a−3p. mmu-miRs-182−5p and -378a−3p were subsequently measured using digital drop PCR across a dose range for DEHP and two related phthalates with weaker PPARα activity, di-n-octyl phthalate and n-butyl benzyl phthalate, following 7-day exposures. Analysis of mmu-miRs-182−5p and -378a−3p by transcriptional benchmark dose analysis correctly identified DEHP as having the greatest potency. However, benchmark dose estimates for DEHP based on these miRNAs (average 163; range 126−202 mg/kg-day) were higher on average than values for PPARα target genes (average 74; range 29−183 mg/kg-day). These findings identify putative miRNA biomarkers of PPARα pathway activity and suggest that early miRNA changes may be used to stratify chemical potency.

Highlights • Contraceptive pill induced hepatocellular adenoma with Turner’s syndrome patient is extremely rare. • However Turner’s syndrome patient requires a lifetime hormone replacement therapy. • Proper diagnosis and treatment plan is necessary for hepatocellular adenoma., Introduction Hepatocellular adenoma (HCA) is a rare benign tumor and is related to the use of an oral contraceptive pill. Turner’s syndrome requires various hormone replacement therapies, including the pill which is used as a female hormone replacement therapy. Herein we report a case of Turner’s syndrome with HCA treated by liver segmentectomy. Presentation of case A 36-year-old woman with Turner’s syndrome was treated with oral contraceptive pills as a female hormone replacement therapy for 20 years. She presented with fatigue and liver tumor. Liver tumors in the posterior lobe measuring 60 mm and 10 mm in diameter were detected on CT; hence, she was referred to our department. Both the tumors showed high intensity in the arterial phase, iso-intensity in the portal and late phases, and low intensity in the hepatobiliary phase on Gb-EOB-MRI. She was diagnosed with multiple HCAs and underwent segmentectomy Section 7. Pathologically, both the tumors were diagnosed as HCAs, and inflammatory markers were detected by immunohistochemistry. Thirteen months postoperatively, she was doing well and there was no evidence of recurrence of HCA without the pill. Discussion There is only one report of HCA in patients with TS (Espat et al., 2000). We reported a case of multiple HCAs in a patient with TS underwent hepatectomy. Conclusion With the use of the contraceptive pill as a long-term female hormone replacement therapy for Turner’s syndrome, careful attention is required for HCA.

Background & Aims Malignant transformation of hepatocellular adenoma (MT-HCA) may occur in up to 5% of tumours. However, the prognostic value of this event remains poorly described. In this study, we aimed to analyse the long-term outcomes of patients undergoing liver resection (LR) for MT-HCA compared to those of patients resected for hepatocellular carcinoma (HCC) occurring on normal liver parenchyma (NP-HCC). Methods This single-centre retrospective study included all patients who underwent LR for MT-HCA at Beaujon Hospital between 2001 and 2019. MT-HCAs were classified as small foci of malignant transformation HCA (SF-HCA) and as malignant HCA (M-HCA) in cases of predominant HCC foci. Recurrence-free survival (RFS) of MT-HCA was compared with that of NP-HCC after propensity score matching. Results Forty patients (24 men, 16 women) underwent LR for MT-HCA, including 23 with SF-HCA and 17 with M-HCA. Of these cases, 16/40 (40%) had β-catenin mutations, 19/40 (47.5%) were inflammatory, 1 was HNF1α-mutated HCA and 4 (10%) were unclassified HCA. Microvascular invasion (12% vs. 0%, p = 0.091) and satellite nodules (25% vs. 4%, p = 0.028) were more frequently observed in M-HCA than in SF-HCA. After a median follow-up of 67 months, 10 (25%) patients with MT-HCA had tumour recurrence, including 9 with M-HCA and 1 with SF-HCA (p = 0.007). M-HCA was linked to significantly poorer 1-, 3-, 5- and 10-year RFS rates than SF-HCA (76%, 63%, 39%, 37% vs. 100%, 100%, 100%, 91%, p = 0.003). Multivariate analysis showed that SF-HCA was independently associated with improved RFS (hazard ratio 0.064; 95% CI 0.008–0.519; p = 0.01). After propensity score matching, NP-HCC was associated with significantly poorer 1-, 3-, 5- and 10-year RFS rates than MT-HCA (p = 0.01). Conclusions HCA with malignant transformation yields a better long-term prognosis than NP-HCC. Among MT-HCA, SF-HCA is associated with a better prognosis than M-HCA. Lay summary The prognostic relevance of malignant transformation of hepatocellular adenoma (HCA) remains unknown. Thus, the aim of our study was to compare the outcomes of patients undergoing liver resection for malignant transformation to those of patients undergoing liver resection for hepatocellular carcinoma (HCC). The main long-term risk after resection for carcinoma is recurrence. In this study, 10/40 patients with malignant transformation of HCA relapsed after resection and we identified age >55 years, presence of satellite nodes, and microvascular invasion as risk factors for long-term recurrence. Compared to patients with HCC, patients who underwent liver resection for HCA with malignant transformation had better long-term survival., Graphical abstract, Highlights • Malignant transformation into hepatocellular carcinoma (HCC) occurs in up to 5% of hepatocellular adenomas. • The main long-term risk after liver resection for carcinoma is recurrence. • Forty patients had liver resection for MT-HCA, including 23 patients with SF-HCA and 17 with M-HCA. • M-HCA was associated with significantly poorer survival than SF-HCA. • Compared to HCC, patients who underwent liver resection for HCA with malignant transformation had better long-term survival.

Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. In a previous 70–90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-α activity in G6pc−/− mice corrects hepatic G6Pase-α deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase-α activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc−/− mice expressing 0.2% of wild-type hepatic G6Pase-α activity suffered from frequent hypoglycemic seizures at age 63–65 weeks but mice expressing 0.5–1.3% of wild-type hepatic G6Pase-α activity (AAV-LL mice) sustain 4–6 h of fast and grow normally to age 75–90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-α/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase-α gene-based therapy for GSD-Ia., Highlights • Establish the minimal hepatic G6Pase-α activity restoration required to provide a blood glucose level that enables GSD-Ia mice grow to old age (75–90 weeks). • Establish the minimal hepatic G6Pase-α activity restoration required that enables GSD-Ia mice grow to old age (75-90 weeks). • Define the lowest dose for G6Pase-α gene therapy that provides efficacy in mice, which informs a phase I/II clinical trial design in human GSD-Ia.