Small-for-size syndrome and hypoxia : a lesson learned from the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) rapid liver regeneration model in rats

In the setting of major hepatectomy, excessive portal perfusion, “dearterialization” and hypoxia of the liver remnant are considered as the main pathogenic mechanisms for the Small for Size Syndrome (SFSS), a potentially lethal clinical entity. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces rapid and enhanced hypertrophy of an insufficient-for-survival future liver remnant. Based on a rodent model of ALPPS that we developed, we compared the remnant’s inflow in ALPPS and in SFSS-setting hepatectomy. We demonstrated that portal hyperperfusion is essential for rapid liver regeneration, and it is not the sole factor for the development of SFSS. Moreover, ‘dearterialization’ and hypoxia in ALPPS remnants improved survival by activation of an early angiogenic response and preservation of the sinusoidal morphology. When we experimentally induced hypoxia in an upfront SFSS-setting hepatectomy, we rescued survival. Activation of hypoxia sensors had no impact on hepatocyte proliferation but surged an early angiogenic switch and preserved the sinusoidal architecture. Hypoxia protects the liver from SFSS. Our study brings experimental evidence that hypoxia-induced angiogenesis balances sinusoidal remodelling to hepatocyte proliferation, preserves the lobular architecture and allows functional liver regeneration after major hepatectomy.