Recurrence of NAFLD and NASH after liver transplantation is not uncommon [5]. Prospective analysis of protocol biopsies reported that 60 % of liver transplants performed for NASH cirrhosis developed steatosis—at least grade 2—at 1-year post-transplant [8]. Additionally, steatohepatitis occurred in over 50 % of patients at 2-year post-transplant. In our experience, 32 % of patients who underwent liver transplantation for NASH-related cirrhosis developed steatosis over a follow-up period of 5.1 (0.69–13.4) months post-liver transplant [9].

Additionally, among liver transplant recipients who underwent liver transplantation for etiologies outside fatty liver disease, ~20 % develop de novo steatosis, and ~10 % de novo steatohepatitis following transplant [10]. This is particularly true in patients with hepatitis C virus infection. Several studies clearly demonstrated a strong relationship between hepatitis C virus infection and the development of insulin resistance and metabolic syndrome [11]. An experimental mouse model transgenic for hepatitis C virus core gene was able to induce insulin resistance and diabetes mellitus [12]. Saab et al. [13] reported that almost 40 % of hepatitis C patients develop new onset diabetes following liver transplantation compared to only 10 % of those transplanted for other indications. A previous publication [14] reported 50 % prevalence of metabolic syndrome in patients with recurrent hepatitis C following liver transplantation. This figure is significantly higher than the prevalence of metabolic syndrome of 22 % in the general US population as reported in the National Health and Nutrition Examination Survey III.

Among the many factors that may potentially predispose to the recurrence or de novo development of fatty liver post-transplant [3, 5, 6], metabolic syndrome is of particular interest. Features of metabolic syndrome are very common and almost universal following liver transplant, Table 10.3 [14–16]. The rate of diabetes after transplant is approximately 40–60 % rising from ~15 % prior to transplant [14]. Summarily, around 60 % of transplant patients develop hypertension. Dyslipidemia occurs in approximately 50 % of patients after transplant. On average, half of liver transplant population reach obesity—defined by body mass index ≥30—by 1 year of liver transplant [14]. Reason is poorly understood but it is believed that lifestyle modifications—namely the return to sedentary normal daily life and free food intake which obviously contribute to the development of weight gain and metabolic risk factors following liver transplantation. Consequently, metabolic syndrome is very prevalent in liver transplant patients ranging from 45 to 58 % at just 6–12 month post-liver transplant—leading to the recurrence or de novo development of fatty liver post-transplant. Seo et al. [10] showed that 10 % increase in body mass index is associated with 20-fold increased risk of the development of fatty liver following liver transplantation. Similarly, we observed a significant association between diabetes, hypertension, and metabolic syndrome and the development of fatty liver disease after transplant [9]. These metabolic risk factors carry an increased risk of hepatic fibrosis following liver transplantation.

Immunosuppressive medications used following liver transplantation may play a significant role in the pathogenesis of fatty liver post-transplant. Corticosteroids are traditionally implicated in the development of steatosis and steatohepatitis, and it has been demonstrated that cumulative use of corticosteroids used following liver transplant is associated with recurrence of NASH post-transplant [9]. Additionally, the use of corticosteroids following liver transplantation has been implicated in the development of fibrosis post-transplant ; this has been well documented in a recent study [9]. This study suggested that the use of corticosteroids post-liver transplant in NASH carries a risk of developing hepatic fibrosis that rivals the risk in patients with post-transplant recurrent hepatitis C virus infection. Based on these findings, immunosuppressant protocols following liver transplant for NASH patients should minimize and shorten the use of corticosteroids when possible. Calcineurin inhibitors are associated with the development of hypertension and glucose intolerance [14], whereas mammalian target of rapamycin (mTOR) inhibitors may lead to dyslipidemia [14]—all may contribute to the development of fatty liver following transplantation.