Authors
A. DILI (1), V. LEBRUN (2), C. BERTRAND (3), I. LECLERCQ (2) / [1] CHU ULC Namur and Laboratory of Gastroenterology, Istitut de Recherche Expérimentale et Clinique, UCL, Brussels, Brussels, Belgium, Surgery and Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium, [2] Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium, Brussels, Belgium, Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium, [3] CHU UCL Namur, Yvoir, Belgium, Surgery
Introduction ALPPS is a surgical technic that combines portal vein ligation (PVL) and parenchymal transection followed by resection of the deportalized liver within 2 weeks. ALPPS achieves rapid hypertrophy of the future liver remnant (FLR) protecting patients from liver failure after extended otherwise non-viable hepatectomy (small for size syndrome-SFSS). SFSS is related to portal hyperperfusion of a very small hepatic parenchyma, with a compensatory constriction of the common hepatic artery (hepatic arterial buffer response-HABR) believed lied to desarterialisation of FLR and postoperative liver failure. In ALPPS, PVL and parenchymal transection redirect the whole portal flow through a small FLR. Despite a growing use of the ALPPS procedure in clinics, consequences on arterial flow and underlying mechanisms for accelerated regeneration and protection from SFSS are still unknown.
Aim
There are reports on animal models for ALPPS, but none accurately mimics the human procedure: rodent models either do not achieve liver resection leaving a small, insufficient for survival, FLR or propose hepatic resection during the first step of ALPPS. Differences in volume of FLR and in surgical events may introduce bias in our understanding of pathophysiological mechanisms. This study aims to develop a model mimicking ALPPS with minimal FLR and to analyze hepatic hemodynamics.
Methods In rodents, the left median lobe (LML), represents 10% of the liver volume. Px90 represents a total hepatectomy except LML, transection (T) a hepatotomy between the right and left segment of median lobe and PVL a ligation of all portal branches except those that perfuse LML. PVLT followed by Px9O is a strict copy of conventional human ALPPS. The first experiment (group A) studied the volume hypertrophy of LML after a unique procedure (T, PVL, PVLT and sham); rats were harvested at 6hours,1,2,3,7days. The second experiment (group B) analyzed mortality and volume hypertrophy after Px90 and two step procedures, PVL-Px90 and PVLT-Px90. Flow rate in portal trunc and common hepatic artery (HA) were measured by US-Doppler in Sham, PVL, PVLT and Px90.
Results In group A, hypertrophy of FLR was greater at day 2 and 3 after PVLT compared to PVL (p<0,05) but not at day 7, suggesting that PVLT accelerated initial hypertrophy. Hepatocyte proliferation, assessed by Ki67 and BrdU IHC, was significantly higher at day 2 and 3 in PVLT remnants (p<0,05). We observed no hypertrophy after T. In group B, ALPPS was associated with a low seven day mortality rate (29.41%) compared to Px90 (77.7%) or PVL-Px90 (38.46%) (p<0.05). Acceleration in regeneration was confirmed by a significantly higher kinetic growth ratio in 1st and 2nd stage ALPPS (PVLT, PVLT-Px90) compared to PVL and PVL-Px90 (p<0,005). Total portal vein flow was similarly reduced after PVL, PVLT and Px90 compared to sham (p<0,001). However, because 90% of the liver parenchyma was excluded from the portal circulation in PVL, PVLT and Px90, the portal flow in the FLR was increased by a factor 4 to 5 compared to flow reaching LML in sham animals (p<0.0001). A decrease in HA flow occurred after PVL and PVLT compared to sham (p<0.001) and was further lowered after Px90 (p<0.5 vs PVLT; p<0.01 vs PVL) suggesting a HABR concommitent to portal hyperperfusion in all 3 procedures. While arterial blood is distributed in the entire liver in PVL and PVLT, it only enters the 10% FLR in Px90, in consequence, effective arterial flow into FLR is increased after Px90, but is halved after PVLT (p<0.05) and decreased in a lesser extend after PVL (p=ns). Immunohistochemistry using pimonidazole (an ischemia marker) demonstrated a significantly higher ischemia at day 1 in PVLT compared to sham, PVL and Px90 (p<0,05).
Conclusions We describe the first animal model with minimal FLR, leading to high mortality due to SFSS unless ALPPS is applied. The degree of liver growth and kinetic growth ratio confirm that ALPPS boosts liver hypertrophy more than PVL. Hemodynamic study suggests that even if HABR exists in Px90, the SFSS consecutive to this kind of marginal hepatectomy is not related to parenchymal desarterialisation; on the contrary, reduction of arterial parenchymal perfusion as observed in PVLT (the first step in ALPPS procedure) may protect the FLR from hepatocellular failure and stimulate regeneration. This model reproduces the objectives intended in human conventional ALPPS and should be valuable for study of physiological mechanisms.