Understanding the meaning of fat in the liver

The growing discrepancy between the number of patients listed for liver transplantation and the availability of cadaveric organs has led to the acceptance by many of living donor liver transplantation (LDLT) as a life saving surgical innovation.1 The most important determinants in recipient outcome after LDLT are the careful selection of living donor and recipient, and the technical skill and experience of the surgical team. While the use of marginal cadaveric donor livers is an appropriate strategy to increase the number of available grafts for transplantation, only perfect “or almost perfect” livers can be used in LDLT, because a healthy living donor is concomitantly placed at risk. The presence of any kind of hepatitis, fibrosis, and moderate / severe steatosis are absolute contraindications for living donation in most centers. However, whether potential donor with mild steatosis (≤30% steatosis) should be denied from donation remains controversial. LDLT, living donor liver transplantation. Steatosis is increasingly prevalent in most societies, and is mainly related to obesity.2-4 For example, 1 out of 5 Americans currently has a body mass index of more than 30 kg/m2, a figure that may reach 40% by the year 2025.5, 6 Of note, not only obesity, but also overweight (body mass index ≥ 25 kg/m2) are independent risk factors for hepatic steatosis.2 The reported incidence of steatosis in donors considered for liver transplantation ranged between 27 and 34%,7, 8 and many of these potential donors are currently denied for donation. In this issue of Liver Transplantation, Cho et al.9 report similar regeneration ability and early outcome between recipients receiving mild steatotic (≤30% macrosteatosis) vs. normal (≤5% macrosteatosis) liver grafts. Using biopsies performed 10 days after surgery, they noted that the degree of steatosis decreased to less than 10% in all grafts, suggesting that mild steatosis is rapidly reversible after LDLT. However, as only 7 patients had a degree of steatosis ranging between 15 and 30%, some caution is needed before these results are widely applied. Donor safety is the 1st priority, and any attempt should be made to prevent liver failure after donor hepatectomy. The remnant liver should exceed 30% of the original liver volume for safe donation.10, 11 Steatosis increases the risk of postoperative complications after liver resection,12, 13 and thus, although the graft may be used with success, the impact of hepatectomy on the donor should be carefully evaluated. While Cho et al.9 focused exclusively on the recipient outcome, the impact of fat on the donor must be 1st evaluated. In absence of solid data, we would contend that the minimal amount of remnant liver in donors with mild steatosis should exceed 40% to avoid additional risk related to steatosis. The ability to detect differences in outcome depends on the definition and accuracy of the endpoints studied.14 Mortality and primary graft nonfunction are usually clearly defined, but no consensus exists regarding delayed graft function. For example, some authors define delayed graft function as impaired liver function responding to support therapy,15 and others as aspartate aminotransferase level >2,000 IU/L or prothrombin time >16 seconds between postoperative day 2 and day 7 after liver grafting.16, 17 Cho et al.9 have selected the criteria proposed by Yersiz et al.,18 in which delayed graft function was defined as marginal graft function necessitating retransplantation within 1 month. The use of this definition might explain the 0% incidence following LDLT in the current study. A better assessment of early graft outcome might be achieved through objective parameters such as ranges of prothrombin time (i.e., <30, 30-50, or >50%) as proposed in the European Liver Transplant Registry.19 We have proposed a therapy-oriented severity-grading classification system to serve as the basis to assess the outcome of liver transplantation.20 This classification was recently updated and validated in a large patient population and through a survey,21 and is currently used to assess the postoperative course of donors in the United States (J. Trotter, personal communication). The application of such a complication system is likely to reveal a higher incidence of complications following LDLT. In addition, information regarding the recipient status prior to liver transplantation (i.e., model for end-stage liver disease or Child-Turcotte-Pugh score status) could help to better define preoperative risk factors affecting early outcome in these patients.22 How to identify fat deposit in hepatocytes and how macro- vs. microsteatosis impacts the outcome after transplantation remains controversial. The use of hematoxylin and eosin–stained sections to evaluate macrosteatosis is appropriate, but largely underestimates the presence of microsteatosis.23, 24 Specific fat staining techniques such as Red-oil-O or Sudan red staining should be preferentially used to assess and quantify all forms of fat deposits in the liver.25 Next, the debate as to whether only macrosteatosis puts the organ at risk (i.e., one can ignore microsteatosis) remains open. Cho et al.9 suggest that only macrosteatosis matters, while others exclude potential donors with >20,26 >25,27 or >30%28 of steatosis, regardless of the qualitative analysis of the fatty liver. Data from the laboratory suggest that both micro- and macrosteatosis negatively impact on ischemic injury29 and regeneration,30 although macrosteatosis is typically associated with worse injury. Convincing clinical data on both types of fat deposits related to outcome is still lacking. Whether a preoperative biopsy is needed for the evaluation of liver steatosis remains under discussion. A survey of U.S. centers performing adult to adult LDLT has highlighted variability in the use of invasive testing such as liver biopsy.1 While some authors perform routine biopsy,28, 31 others use it selectively; for example, in the presence of a body mass index >28 kg/m232 or when steatosis is suggested by radiological examination.26, 32 A biopsy may also cause bias, as intrahepatic heterogeneity may lead to under- or overestimation of steatosis.33, 34 Cho et al.9 propose selective biopsies based on 3 components: body mass index, computed tomogram assessing liver/spleen ratio, and liver attenuation index. As noninvasive methodology has failed to predict mild and also moderate steatosis in potential donor livers,35 this approach should be used only to exclude patients with severe steatosis (>60%) during preoperative workup. Liver biopsy is also indicated to detect other pathologic conditions such as hepatitis, fibrosis, or other incidental liver diseases.31, 36 In our institution, as in many others,31, 37, 38 we still perform routine liver biopsy as the last test in the workup of potential donors. Alternative strategies have been proposed to circumvent the risk associated with steatosis in potential donors. In the presence of fatty liver, a certain period of diet and physical exercise therapy could permit reduction of liver steatosis, allowing a delayed but safer living donation.33, 34 Another approach proposed by Marcos et al.28 is to integrate the degree of steatosis into the estimated graft–recipient body weigh ratio by simply assuming that for each percent of fat, the viable liver mass decreases by 1%. In conclusion, Cho et al.9 provide interesting clinical data suggesting the safe use of liver grafts with mild macrosteatosis for living donation. Future studies with larger patient populations are needed to confirm this finding, and the impact of macrosteatosis on the outcome of hepatectomy in the donor must remain the 1st priority. Future studies also need to assess how microsteatosis may impact the outcome of LDLT, and particularly how the combination of both types of steatosis may influence ischemic injury and regeneration. In such studies, the appropriate staining to identify fat deposits in the liver will be paramount for conclusive results.