The outcomes of adult living donor liver transplantation (ALDLT) are equivalent to the outcomes of deceased donor liver transplantation in similar patient populations at experienced centers.1 Because of the organ shortage, most transplant centers are confronted with the need to perform transplantation for patients on the waiting list before they die or become too ill. Ultimately, it is the combined mortality of patients on the waiting list and posttransplant mortality, which determines the efficacy of liver replacement therapy. With the current ALDLT crisis in Western countries, it is imperative to develop reliable strategies that lead to successful outcomes and, at the same time, reduce the risks for living donors. On the basis of donor morbidity data for ALDLT from American and Asian surveys (1957 patients), we can calculate a reduced morbidity rate for left lobe donors versus right lobe donors (21% versus 11.5%).2, 3 Data from the European Liver Transplant Registry show similar results.4 The widespread use of left lobes has been limited because they are smaller and are potentially insufficient for the metabolic demands of recipients. Currently, a donor liver is considered a small-for-size graft (SFSG) when the graft-to-recipient weight ratio is less than 0.8 or the ratio of the graft volume to the standard liver volume is less than 40%. Nevertheless, the graft size is only one of the factors required for successful ALDLT. Because of the vast potential pool of living donors and the inferior risk associated with left liver donation, a strategy for transplanting SFSGs safely into adult recipients could effectively address the donor shortage and potentially reduce mortality on the waiting list. Despite the statistically significant negative impact of SFSGs on graft prognosis and patient outcomes, success with these grafts was observed in early reports. Nishizaki et al.5 recorded no graft losses in 5 patients receiving SFSGs with graft volume to standard liver volume ratios of 26% to 29% in 2001. Likewise, in 2003, Kiuchi et al.6 reported 4 successful instances in which SFSGs were used in recipients with various pretransplant statuses; the lowest graft-to-recipient weight ratio was 0.59. These findings suggest that although recipients of SFSGs are at higher risk for worse outcomes, the small size of the grafts is not always solely responsible.7 Factors other than the graft volume can potentially influence the outcome; these include recipient-related factors (disease clinical status and portal hypertension), graft-related factors (donor age, steatosis, cold and warm ischemia times, ischemia/reperfusion injury, and immunological factors), and technical factors (vascular reconstruction and adequate outflow, vascular inflow, and pressure gradients). All these factors contribute to the concept of functional graft size, and even a larger graft can fail when multiple risk factors are present.
During the last decade, controversial results have been reported about outcomes with SFSGs. The lowest 1-year graft survival rates have ranged from 33% to 65%,8-15 and the highest rates have ranged from 75% to 100%.16-24 Graft failure due to the use of SFSGs has been described as small-for-size syndrome (SFSS). The incidence of SFSS in these reports has greatly varied and has ranged from 13.6% to 100%. These discrepancies may be adequately explained by the different criteria used to define SFSS and by the lack of uniformity in reporting recipient-related, graft-related, and technical factors.
Experimental studies have shown that portal hyperperfusion is detrimental, especially for SFSGs.25-32 This excessive portal inflow is thought to be a primary factor in the dysfunction and failure of SFSGs. The reduction of the intrahepatic vascular bed results in higher portal flow per 100 g of liver tissue, a rise in the portal pressure, and stress at the hepatic sinusoid.10, 11, 21, 33, 34 Reduced hepatic artery flow after increased portal flow has been described.35, 36 This imbalance, which has been observed with all graft types, is markedly increased in partial grafts.37 To reduce the risk for these stress factors, different graft inflow modulation (GIM) techniques are currently being used.12, 21, 38-42 When SFSGs are used without the application of any GIM technique, we may pay a steep price in graft survival (from 100% to 38%).10, 12, 17, 18, 20, 21, 23, 43, 44
In this issue of Liver Transplantation, Ishizaki et al.45 present their successful single-center experience with ALDLT and left livers, allegedly without GIM. This poses the question whether GIM is necessary. The authors describe 17 patients (40% of their study population) with SFSGs; for only 3 of these patients (18%) was the Model for End-Stage Liver Disease score greater than 20. The highest reported flow (833 mL/minute/100 g of liver) represents a value that puts the graft at risk. Because it is indexed by the graft weight, this flow probably corresponds to recipients of the smallest grafts; 4 of these patients underwent GIM by means of splenic artery ligation (SAL). Regardless of the indication, SAL is a GIM technique that potentially influences the outcome. Unfortunately, no data are provided about flow or gradient measurements before and after SAL to dissipate this doubt. Also, the fact that SAL patients did not show any significant differences in pressure gradients in comparison with non-SAL patients merits further discussion. The gradients and the pressures were 10 mm Hg higher in SAL patients (as could be expected in patients with marked splenomegaly). Therefore, an effect on the outcome due to a reduction of hyperflow and/or portal hypertension cannot be ruled out unless measurements of flows and gradients are performed before and after SAL. Similarly, the percentage of patients with intractable ascites was twice as high as the percentage of patients with severe portal hypertension, and the lack of statistical significance could be attributed to the limited patient population. Fortunately, all the patients recovered.
Do we need GIM when we are transplanting SFSGs? Good results have indeed been described without the use of GIM. In addition to technical and graft-related factors, a patient's metabolic requirements due to the disease stage, the presence of portal hypertension, and the hyperdynamic status play major roles in the stress that an SFSG can tolerate. Accordingly, the size of the graft is not the only factor determining the outcome, and the functional size has to be taken into account. If hemodynamic stress is identified, GIM could be applied to decrease it. Nevertheless, GIM does not guarantee adequate regeneration and function in the sickest patients. New combined strategies of pharmacological flow and pressure gradient modulation and pharmacological protection for reducing ischemia/reperfusion injury could be extremely important for the regeneration and function of SFSGs in sick patients.48-50 Such approaches could increase the use of left liver grafts and lead to good expected outcomes and a reduction of living donor morbidity.