Maturity of associating liver partition and portal vein ligation for staged hepatectomy-derived liver regeneration in a rat model

Abstract

AIMTo establish a rat model for evaluating the maturity of liver regeneration derived from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).METHODSIn the present study, ALPPS, partial hepatecotmy (PHx), and sham rat models were established initially, which were validated by significant increase of proliferative markers including Ki-67, proliferating cell nuclear antigen, and cyclin D1. In the setting of accelerated proliferation in volume at the second and fifth day after ALPPS, the characteristics of newborn hepatocytes, as well as specific markers of progenitor hepatic cell, were identified. Afterwards, the detection of liver function followed by cluster analysis of functional gene expression were performed to evaluate the maturity.RESULTSCompared with PHx and sham groups, the proliferation of FLR was significantly higher in ALPPS group (P = 0.023 and 0.001 at second day, P = 0.034 and P < 0.001 at fifth day after stage I). Meanwhile, the increased expression of proliferative markers including Ki-67, proliferating cell nuclear antigen, and cyclin D1 verified the accelerated liver regeneration derived from ALPPS procedure. However, ALPPS-induced Sox9 positive hepatocytes significantly increased beyond the portal triad, which indicated the progenitor hepatic cell was potentially involved. And the characteristics of ALPPS-induced hepatocytes indicated the lower expression of hepatocyte nuclear factor 4 and anti-tryptase in early proliferative stage. Both suggested the immaturity of ALPPS-derived liver regeneration. Additionally, the detection of liver function and functional genes expression confirmed the immaturity of renascent hepatocytes derived in early stage of ALPPS-derived liver regeneration.CONCLUSIONOur study revealed the immaturity of ALPPS-derived proliferation in early regenerative response, which indicated that the volumetric assessment overestimated the functional proliferation. This could be convincing evidence that the stage II of ALPPS should be performed prudently in patients with marginally adequate FLR, as the ALPPS-derived proliferation in volume lags behind the functional regeneration.

Functional and volumetric assessment of liver segments after portal vein embolization: Differences in hypertrophy response

“…In the early proliferative stage after ALPPS-stage 1, the increase in volume is the result of proliferation of hepatocytes that are enlarged but have not yet undergone full maturation. 20,21 As hepatocytes mature, the functional increase will likely catch up with the volume increase. Of note, the differentiation of hepatocytes in ALPPS appears to be more prolonged than after hepatectomy.…”

“…Of note, the differentiation of hepatocytes in ALPPS appears to be more prolonged than after hepatectomy. 20 Whether the dynamics of these growth patterns are comparable in patients undergoing PVE remains unknown. In this study, the first measurement of both volume and function was conducted 3 weeks after PVE.…”

A preliminary study of associating liver partition and portal vein ligation for staged hepatectomy in a rat model of liver cirrhosis

“…Finally, the authors observed a similar increase in FLV to the ALPPS group, indicating that localized trauma or inflammatory responses might accelerate the induction of hepatocyte proliferation (19). Almau et al (36) and Tong et al (37) established a rat experimental model based on the ALPPS procedure as described above. Furthermore, Yao et al (38) revealed that the reactivation rate of the liver was significantly faster in the ALPPS group on the 3rd and 7th postoperative days compared with the PVL group.…”

ALPPS for hepatocarcinoma under cirrhosis: a feasible alternative to portal vein embolization

“…The fibrotic tissue ends up hindering liver regeneration (72). Although previous cirrhosis would limit in principle the process of hypertrophy, the degree of hypertrophy induced by ALPPS could be beneficial even for cirrhotic patients (59,73,74). However, discordance between the growth in liver volume in ALPPS and the functional growth of the proliferated liver has been detected, with multiple signs of immaturity in the tissue being appreciated (73,(75)(76)(77).…”