Changes in hepatic iron homeostasis predict the ability to successfully withdraw immunosuppression following liver transplantation

▶ Bohne F, Martinez-Llordella M, Lozano JJ, et al. Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation. J Clin Invest 2012;122:368–82.

Modern immunosuppressive regimes have vastly improved outcomes following liver transplantation. However, long-term immunosuppression has potential adverse consequences, including increased risk of infection, cardiovascular disease and malignancy. It is therefore fascinating that recent evidence indicates that a proportion of liver transplant patients (around 25%) can achieve stable graft function following complete withdrawal of immunosuppression (termed clinical operational tolerance). The ability to predict which patients will achieve operational tolerance and the mechanisms governing this process remain elusive. In this article, Bohne et al have addressed these key issues. They collected blood and liver tissue samples from liver transplant patients enrolled in a prospective immunosuppression withdrawal trial. Of the 75 patients with liver tissue available, 33 successfully discontinued immunosuppression (operationally tolerant), while 42 developed rejection (non-tolerant). Non-biased whole transcriptome analysis of liver tissue prior to stopping immunosuppression, comparing patients who were operationally tolerant with those who were non-tolerant, demonstrated a clear difference in expression of genes involved in iron homeostasis between the two groups. Specifically, tolerant livers showed higher levels of hepcidin and lower levels of transferrin receptor expression, along with differences in a number of other iron-regulating genes. These findings were extensively validated and indeed histological analysis demonstrated increased periportal hepatocyte iron deposition in tolerant patients, with no discernible change in immune cells. Serum analysis demonstrated that non-tolerant patients had lower circulating levels of hepcidin and ferritin. Using these data, the authors identified gene expression signatures to accurately predict operational tolerance in an independent cohort of patients. Clearly, this study needs further validation in larger patient groups with long-term outcome data. However, it offers the tantalising possibility in clinical …