Liver transplantation for fatty liver disease

Abstract

As the incidence of obesity continues to rise in the USA and around the world, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are increasingly diagnosed and recognized as a cause of end-stage liver disease (ESLD). The increasing utilization of liver transplantation (LTX) to treat patients with ESLD due to NASH is tempered by the documentation of a recurrence of NAFLD after LTX, which can compromise post-transplant outcomes. Furthermore, the growing obesity epidemic also affects the donor pool. The use of fatty donor livers for LTX is associated with an increased risk of primary non-function (PNF), not only for brain-dead but also living donor liver allografts. The purpose of this review is to examine the outcomes of LTX in patients transplanted with NAFLD and NASH. The first report identifying recurrent NAFLD after LTX was made in 1996.1 Excluding patients with significant alcohol consumption, eight of 622 explanted livers had features consistent with NASH. Interestingly, all the patients involved were female. Although early failure (a median follow up of 15 months) was not seen, six patients developed fatty infiltration in the transplanted graft consistent with a diagnosis of recurrent NASH. In addition, the progression of mild steatosis to steatohepatitis and early fibrosis was observed in two patients. A larger, single-center study of a cohort from the University of Pittsburgh2 found that of 98 patients transplanted for NASH, recurrent NAFLD was seen in 70% and recurrent NASH was found in 25 and 18% of patients with stage II–IV or greater fibrosis at a mean of 18 months post-LTX, respectively. In spite of this, no patients developed graft failure in 3 years of follow up. Finally, one important finding of this study, which impacts on the protocols for follow up in these patients was that one-third of patients with recurrent NASH had normal liver function tests at the time of diagnosis post-transplantation. Lastly, the Baylor group noted that in patients with recurrent NASH, up to 30% developed bridging fibrosis or cirrhosis after 10 years.3 Dumortier et al. identified seven risk factors for the development of recurrent NAFLD after LTX: (i) post-LTX obesity; (ii) tacrolimus-based immunosuppression; (iii) diabetes mellitus; (iv) hyperlipidemia; (v) arterial hypertension; (vi) alcoholic cirrhosis as a primary indication for LTX; and (vii) pre-transplant liver graft steatosis. When zero, one, two, three, four, five and six factors were present, steatosis occurred in 6, 12, 22, 30, 66, 82, and 100% of patients, respectively4 Morbidity after LTX differed in the NASH group compared to a group of patients with alcoholic liver disease, with a higher risk of cardiovascular events (26 vs 7% in the ethanol group, P = 0.21), as well as with a higher risk of rejection (41 vs 23%, P < 0.023) in this group compared to those with alcoholic liver disease.5 In LTX patients who gain significant weight in the post-transplant period, the de novo development of NAFLD was recently studied.6 In a retrospective analysis of 68 LTX patients a total of 12 patients (18%) developed de novo NAFLD, and six (9%) developed de novo NASH. By regression analysis, they found that the use of angiotensin-converting enzyme inhibitors (ACE-I) was associated with a reduced risk of developing NAFLD after LTX (OR 0.09; P = 0.042). A 10% or more increase in body mass index (BMI) after LTX was associated with a higher risk of developing NAFLD (OR 19.38; P = 0.001). This suggests that the use of an ACE-I may reduce the risk of developing post-LTX NAFLD. Although recurrent NAFLD after LTX appears to have a limited effect on long-term survival, its added morbidity and long-term impact on survival has yet to be fully assessed. Nevertheless, as the risk factors are identified, the impact of modulating these risk factors must be considered, as there are major implications on changing the natural course of NAFLD and NASH in post-transplant patients. In addition, while the pathophysiology of NAFLD and NASH has not been clearly elucidated,7 a recapitulation of the processes of NASH following LTX may aid in formulating new approaches to treating NAFLD and NASH in the non-transplant group, such as the use of glitazones8 or vitamin E.9