Triggered Liver Regeneration: From Experimental Model to Clinical Implications

Abstract

Background: Major liver resection is the only therapeutic option for patients with malignant liver tumors. However, extended hepatectomy often leads to postoperative liver failure, mainly due to insufficient amounts of the remnant liver. Recently, selective portal vein occlusion (PVO) has been introduced to increase the remnant liver volume. This novel surgical technique initiated a progressive development in liver surgery, resulting in a significant increment in potential candidates for curative liver resection. Summary: The theoretical basis for this great advancement is formed by an understanding of the mechanisms of PVO-induced liver regeneration, mainly obtained from animal studies. The aim of this review is to give a comprehensive overview of the relevant animal models of PVO and to discuss the main characteristics of triggered liver regeneration, including the induced hemodynamic, morphological and functional alterations as well as the underlying molecular mechanisms, which might be of interest in both the laboratory and the clinic. Key Messages: Although basic research revealed the main characteristics of PVO-triggered liver regeneration within the last decades, several important issues regarding the regenerative process remain uncertain. To answer these open questions, additional well-designed animal experiments are needed in the future, which allow further refinement of this surgical technique.

Animal Models for Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS): Achievements and Future Perspectives

“…After classic PVO techniques - especially following PVL when proximal, extraparenchymal PVO is performed - reperfusion of intraparenchymal portal branches of the occluded part of the liver is possible via already-existing as well as newly formed portoportal collaterals mitigating the induced hemodynamic changes [37]. In the case of ALPPS, ISS abolishes intraparenchymal portoportal shunts, thus resulting in more blood flowing through the FLR.…”

Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in the Rat

“…Future liver remnant enlargement via PVO remains the sole curative option for a wide range of patients with liver malignancies [3, 7, 29]. During the induced liver regeneration process, the precise alterations of hepatic drug metabolism are still incompletely understood, despite its key role in both hepatic function and the metabolism of endogenous and exogenous compounds [30].…”

“…Eventually, the LL undergoes atrophy and underlying necroapoptotic cell death, meanwhile the NLL displays an intensive cellular proliferation and hypertrophy [21, 29], which was repeatedly proven by the literature [2, 5, 29, 30] and previous reports of our workgroup [20, 21, 31]. In the present study, it was similarly reflected by liver lobe weights, thereby validating the standard application of the PVL model, and allowing further, more sophisticated analysis.…”

“…Perhaps the most striking observation is the dramatic difference of lobar responses, as part of which drug metabolism in the LL was permanently deteriorated, whereas it was re-established in the NLL, which may be explained by the far-reaching effects of PVL. Beyond the seemingly solitary action of portal blood flow stoppage to the LL, PVL induces a chain of events, such as the complete redistribution of the splanchnic circulation (arterialized hypoperfusion of the LL; massive portal hyperperfusion of the NLL) and modification of blood decomposition, by which the NLL receives an increased portion of nutritional agents, growth factors, hormones, and bacterial products [29]. These culminate in the induction of a very special form of liver regeneration characterized by the atrophy-hypertrophy complex [29, 35], and diverse pathophysiological changes of structural and microvascular remodeling within the LL and the NLL [20, 29], which may ultimately explain the different functional capacities of the LL and the NLL [31, 35].…”

“…During different pathophysiological conditions such as infection, inflammation, and cancer, increased levels of circulating proinflammatory cytokines lead to CYP downregulation [17, 36] through the repression of nuclear receptors (pregnane X receptor and constitutive androstane receptor) involved in transcriptional regulation of several CYPs (CYP2B, CYP2C, CYP3A) [37, 38]. Meanwhile, the same cytokines, as well as nitric oxide, also play a central role in the initiation and mediation of liver regeneration after both partial hepatectomy and PVO, when their serum levels are sharply increased secondary to inflammatory activation and hemodynamical changes, respectively [29, 35, 39]. Therefore, it is highly plausible that increased levels of inflammatory cytokines as well as nitric oxide may be partly responsible for the transient deterioration of CYP function following PVL.…”