O28 Variability in liver anatomy and physiology in children participating in pharmacokinetic studies

BackgroundObesity-related changes in liver anatomy and physiology (e.g., hepatic fat infiltration) may be important sources of interindivdual variability in hepatic drug metabolism and relevant covariates for physiologically-based pharmacokinetic (PBPK) models. The aim of this investigation was to quantify variability in hepatic fat fraction (HFF) and hepatic volume in children participating in PK studies, utilizing a novel, non-invasive, magnetic resonance imaging (MRI) sequence.1MethodsChildren, without a known diagnosis of fatty liver disease, enrolled in a PK study for hepatic CYP2C19 and CYP3A4 substrates, had hepatic volume and total HFF estimated using MRI proton density fat fraction (PDFF) and HFF assessed via conventional MRI spectroscopy (MRSFF) using a region of interest in the right upper hepatic lobe (LiverLab, Siemens Healthcare). Patient anthropometrics, laboratories and LiverLab outcomes were compared between obese and non-obese children, using independent student t-test, and associations explored via Spearman’s correlation (ρ); SPSSv24, α=0.05. Obesity was defined by body mass index (BMI)≥95th percentile for age; clinically significant liver adiposity defined as HFF>5%.Results25 children (7–20 years; 56% obese) had evaluable MRI data. Liver volume ranged 911–2227cm3, MRSFF 1.6–34.8% and PDFF 2.1–31.1%. Liver volume and HFF significantly correlated with BMI (both ρ=0.6, p< 0.01), but not age (both ρ=0.3, p>0.11). Liver volume (1574.5±367.1 vs 1284.8±216.3, p=0.04), MRSFF (8.9±8.4 vs 2.8±1.2, p=0.02), PDFF (8.9±7.0 vs 3.4±1.3, p=0.07) and alanine aminotransferase (ALT; 37.7±15.8 vs 26.8±3.6 IU/L, p=0.02) were higher in obese vs non-obese children. HFF>5% and ALT> 40 were only observed in obese children.ConclusionLiver volume and adiposity varied substantially among children and may be important covariates for pediatric PBPK models, especially for obese children. HFF> 5% and ALT> 40 were only observed in obese children. Recently, 24% reduction in clearance of azithromycin, a CYP3A4 substrate, was reported for children with ALT> 40.2 Our PK analyses are in progress.ReferencesCaussy C, Reeder SB, Sirlin CB, et al. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as as endpoint in NASH trials. Haptology 2018;68(2):763–72.Zheng Y, Liu SP, Xu BP, et al. Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia. Antimicrob Agents Chemother 2018;62 (9):e00686–18.Disclosure(s)Nothing to disclose

Kinetics of Hepatic Volume Evolution and Architectural Changes after Major Resection in a Porcine Model

Background: The hepatic volume gain following resection is essential for clinical recovery. Previous studies have focused on cellular regeneration. This study aims to explore the rate of hepatic regeneration of the porcine liver following major resection, highlighting estimates of the early microarchitectural changes that occur during the cellular regeneration. Methods: Nineteen large white pigs had 75% resection with serial measurements of the hepatic volume, density, blood flow, and architectural changes. Results: The growth rate initially was 45% per day, then rapidly decreased and was accompanied by a similar pattern of hepatic fat deposition. The architectural changes showed a significant increase in the Ki67 expression (p < 0.0001) in the days following resection with a peak on the 2nd day and nearly normalized on day 7. The expression of CD31 increased significantly on the 2nd and 3rd days compared to the pre-resection samples (p = 0.03). Hepatic artery flow per liver volume remained at baseline ranges during regeneration. Portal flow per liver volume increased after liver resection (p < 0.001), was still elevated on the 1st postoperative day, then decreased. Correlations were significantly negative between the hepatic volume increase on day 3 and the hepatic oxygen consumption and the net lactate production at the end of the procedure (r = –0.82, p = 0.01, and r = –0.70, p = 0.03). Conclusion: The volume increase in the first days – a fast process – is not explained by cellular proliferation alone. The liver/body weight ratio is back to 50% of the preoperative value after 3 days to close to 100% volume regain on days 10–15.

Late results of embolization of a portal hepatic vein branches in patients, suffering extended hepatic tumors

Objective. To analyze late results of preoperative embolization of the portal hepatic vein branches (EPHVB) in patients, suffering extended hepatic tumors and extremely border-like small calculated residual hepatic volume(CRHV). Маterials and methods. From 2004 to 2014 yr the extended hepatic resection (HER) was performed in 285 patients, to whom EPHVB was applied (the main group), аnd in 353 patients as well, but without endovascular preparation (control group). In both groups dynamics of laboratory indices, structure of complications and lethality, late survival were studied. Results. In the main group a trustworthily lower rate of an acute hepatic insufficiency and connected with a lower postoperative lethality - accordingly 2.3 and 4.6%, comparing with a control group - 9.3 and 8.8%, were suggested. The laboratory data dynamics have witnessed a lesser intensiveness of postoperative hepatocytolysis and lesser degree of the hepatic synthetic function lowering in the main group, what have confirmed a better functional adaptation of hepatic residual in patients, to whom preoperative EPHVB was applied. Conclusion. Preoperative EPHVB permits to lower the postoperative complications and lethality rate in patients, suffering hepatic tumors, due to better functional adaptation of hepatic residual.