In liver transplantation, the correct matching between the graft weight and the recipient body weight is pivotal for the subsequent graft function and survival, especially in case of partial grafts. In particular, in living donor liver transplantation (LDLT), a graft-to-recipient body weight ratio (GRBWR) ≤0.8 is associated with graft dysfunction or failure, known as small-for-size syndrome (SFSS).
Portal hyperperfusion is recognized as the main pathogenic factor of the SFSS, which can impair the graft by activating different and concurrent pathways. It triggers an arterial buffer response, a hemodynamic response mediated by the adenosine washout which limits the liver arterial inflow to maintain constant the total-blood liver inflow. The reduced arterial inflow limits the oxygen supply to the graft, with subsequent graft impaired function and regeneration, parenchymal damage and ischemic cholangitis. In addition, the reduced vascular bed of the SFSS graft cannot accommodate the unmodified recipient portal flow. This results in a sudden increase in portal pressure and graft hyper-perfusion, which rises the friction forces (shear stress) on the vascular endothelium. Within physiologic limits, an increased shear stress represents the main factor inducing liver regeneration. However, beyond a certain threshold, an excessive shear-stress impairs the endothelium, with the subsequent edema worsening the graft function, and the activation of an intra-graft response. This response has been recently partially characterized and is mediated by an upregulation of endothelin 1 (ET1) and downregulation of heme oxygenase 1 and Heat shock protein 70, with loss of cellular homeostasis. ET1 determinates vasoconstriction by acting on vascular smooth cells and on hepatic stellate cells (HSC), which contract to determine sinusoidal constriction.
The surgical inflow modulation, through splenic artery ligation and porto-systemic shunts is currently the standard of prevention of SFSS. However, a pharmacological intervention for SFSS would be ideal, for the easy administration and reversible nature. The intra-graft response and its mediators represent potential targets for pharmacological interventions in the SFSS, which could act in conjunction with, or even replace, the surgical inflow modulation. Several molecules have been tested in animal models, including intra-arterial administration of adenosine and nitric oxide (NO) donors, showing effectiveness in reducing the SFSS damage. However, their potential clinical use remains doubtful for safety reasons. Somatostatine and statins, two largely used clinical drugs also promote themselves as potential therapeutics in SFSS.
Statins are able to reduce portal pressure in patients with portal hypertension by lowering intrahepatic resistances. Statins act by decreasing HSC contraction, the ET1 production and by increasing the expression and the activity of the endothelial NO synthase. This clinical and biological evidence supports the use of statins in SFSS and in-vivo animal studies are ongoing.
Similarly, somatostatin inhibits ET1-induced HSC contraction. In addition, in experimental models SST reduced the acute injury due to acute shear-stress resulting from transient portal hypertension 22. There are also some clinical reports supporting a role of SST as a treatment for an already established small-for-size syndrome. We recently conducted a randomized placebo-controlled trial to assess, in a double-blind manner, the efficacy and safety of somatostatin as liver inflow modulator in the setting of LT for clinically significant portal hypertension. After graft reperfusion, somatostatin infusion improved the decrease in portal gradients respect to placebo (- 81.7% vs -58.8%), and preserved the graft arterial inflow (+35% relative increase); in addition somatostatin reduced postoperative portal vein velocity. Compared to placebo, no difference in the incidence of 90-days postoperative adverse and serious adverse events, long term complications, graft and patient survivals were observed.
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Man K et al. Graft Injury in Relation to Graft Size in Right Lobe Live Donor Liver Transplantation Ann Surg 2003;2:256–264
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Abraldes et al., Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009, 136 (5): 1651-68
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Xu X, Man K, Zheng S Sen, et al. Attenuation of acute phase shear stress by somatostatin improves small-for-size liver graft survival. Liver Transpl 2006;12:621–7.
Ozden I, Kara M, Pinarbasi B, et al. Somatostatin and propranolol to treat small-for-size syndrome that occurred despite splenic artery ligation. Exp Clin Transplant 2007;5:686–9.