© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Clin Transplant 2015: 29: 728–737 DOI: 10.1111/ctr.12585

Clinical Transplantation

Review Article

Non-alcoholic fatty liver disease following liver transplantation: a clinical review Merola J, Liapakis A, Mulligan DC, Yoo PS. Non-alcoholic fatty liver disease following liver transplantation: a clinical review. Abstract: Non-alcoholic steatohepatitis (NASH) is rapidly becoming the leading indication for liver transplantation (LT) in the United States. While post-transplantation outcomes are similar to other indications for transplant, recent evidence has suggested that reduction in risk factors for post-transplant metabolic syndrome may impose a significant survival benefit in this patient population. Cardiovascular mortality is the leading cause of death following transplantation for NASH. While pretransplant pharmacologic and surgical approaches have been utilized to reduce cardiovascular risk factors following transplantation, the effectiveness of these treatment approaches in the post-transplant setting is poorly defined. Studies are urgently needed in the treatment of this rapidly growing population.

Jonathan Merolaa, AnnMarie Liapakisb, David C. Mulligana and Peter S. Yooa a

Section of Transplantation and Immunology, Department of Surgery, Yale University School of Medicine and bDivision of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA Key words: fatty liver disease – non-alcoholic steatohepatitis – transplantation Corresponding author: Peter S. Yoo, MD, Assistant Professor of Surgery, Section of Transplantation and Immunology, PO Box 208062, New Haven CT 06520-8062, USA. Tel.: +1 203 785 2565; fax: +1 203 785 5950; e-mail: [email protected] Conflicts of interest: None. Accepted for publication 30 June 2015

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of histologically defined steatotic liver disease that occurs in the absence of significant alcohol consumption. Mild disease may include mild macrovesicular steatosis, whereas severe disease involves hepatocyte ballooning and lobular inflammation, which may lead to end-stage liver fibrosis or cirrhosis. Since Ludwig’s formal description of NAFLD pathology in the late 1980s, the prevalence of non-alcoholic steatohepatitis (NASH) has significantly increased and is currently the second most common etiology of liver disease among waitlisted liver transplant (LT) patients (1–3). It is expected that NASH cirrhosis will become the leading indication for LT in the coming decade (1). Paralleling this trajectory, the development and/or recurrence of NASH after transplant is certain to impose significant challenges (4, 5). The recipient’s genetic predisposition,

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immunosuppressive regimen, and graft steatosis all play a role in the development of NASH after LT. Significant efforts must be put forth to understand, identify, and treat NASH and its associated risk factors in this unique and rapidly growing population. This article aimed to summarize the current clinical knowledge with particular emphasis on risk factors for the development and treatment of NASH following LT. Demographics and prevalence

Worldwide prevalence of NAFLD ranges from 10 to 24%, while among the obese population, prevalence ranges from 57–74% (4). NASH comprised 1.2% in 2001 among all disease etiologies leading to LT, and rose to 9.7% in 2009 (1). This increased frequency is only partially accounted for by the fact that patients with NASH may have been

NAFLD following liver transplant previously characterized as having cryptogenic cirrhosis, as the increased frequency of NASH (1 percentage point/yr) is double the declining frequency of cryptogenic cirrhosis (0.5 percentage point/yr). Projections put forth by Charlton et al. demonstrate that nearly 25 million Americans will develop NASH by 2025, among which nearly one in five will develop cirrhosis and/or hepatocellular carcinoma (HCC) (1). These rates parallel the rapidly increasing rate of risk factors for NASH development. Diabetes mellitus, dyslipidemia, and obesity (BMI >30 kg/m2) are prominent demographic features associated with NASH and progressive liver-related mortality (4). Female gender, older age, obesity, and diabetes are more common among patients with NASH requiring LT, compared to other patients with end-stage liver disease (1). While the frequency of HCC is significantly lower in patients with NASH compared to other patients with end-stage liver disease, hypertriglyceridemia, diabetes, and normal transaminase levels have been shown to be independent factors associated with HCC development in this population (6). Patients transplanted for NASH cirrhosis are prone to recurrence of liver disease due to persistence of their metabolic risk factors that are often exacerbated by immunosuppressive treatments. Defined by the components of central obesity, hyperglycemia, low HDL cholesterol, hypertriglyceridemia, and hypertension (HTN), criteria for metabolic syndrome (MS) are met by 40–60% of transplant recipients, significantly higher than the general population incidence of 30–35% (7). Among patients listed for LT with MS, the vast majority are listed with a diagnosis of viral and alcoholic hepatitis, while only 7.6% were listed with a diagnosis of NASH or cryptogenic cirrhosis (7). A proposed explanation for this discrepancy is that many potential LT candidates with NASH are excluded from transplantation based on comorbid cardiovascular conditions (8). Recurring cirrhosis in patients with NASH has been noted in up to 13% of patients after a mean 28-month follow-up with 0–5% of patients having recurrence-associated graft loss (1, 9–13). Diagnosis

Histological evaluation is the gold standard for the diagnosis of NASH, although it is only performed in selective cases due to limited treatment options, procedural risks, and cost (14). Steatosis is a prerequisite for NASH diagnosis, although its presence alone may be reversible and is not always of clinical consequence (15). The presence of >50%

hepatocellular adiposity has been used as a benchmark to render a diagnosis of fatty liver (15). Diagnosis of NASH requires hallmarks of hepatocyte ballooning and lobular inflammation in addition to macrovesicular steatosis (14). NASH exists as a continuous spectrum of severity. Steatosis and active inflammation evident in early stages of NASH are often not apparent in end-stage cirrhosis (16, 17). The progression of NASH to cirrhosis involves the loss of fat infiltration and, in parallel, the reversal of steatosis noted on histology, posing a challenge to pathologic diagnosis as liver fibrosis advances (18). While the cause for the regression of steatosis has not fully been elucidated, both the lower exposure to insulin and loss of sinusoidal fenestrations that impair passage of lipoproteins are two consequences of diminished portal flow that have been identified as potential contributors to this phenomenon (19–21). All patients with NAFLD have a higher mortality compared to the general population. Prognosis varies between NAFLD and NASH as cirrhosis develops in 3–4% of patients with NAFLD and up to 20% of patients with NASH (22). A high interobserver variability has been described in identification of ballooning hepatocytes and lobular inflammation (16, 23). To aid in this challenge, a recently developed clinical system by Kleiner et al. has been established to achieve reproducibility in diagnosis, known as the NAFLD activity score (23). This relies on identifying the grade of steatosis, extent of inflammation, and degree of hepatocyte ballooning and fibrosis. NASH in the post-transplant setting is almost always preceded by steatosis, and in consequence, protocol biopsy is useful in documenting disease progression (16). Associated inflammation secondary to acute cellular rejection and chronic hepatitis poses a challenge in histological interpretation of biopsy in post-transplant patients (16). The presence of particular histologic features has not been correlated to the severity of liver disease in transplanted livers (16). Recurrent steatosis is often mild in patients with NASH in the early post-transplant period, while >50% steatosis may be observed one yr after transplantation (16). The long-term implications of histologic findings have not been well defined. While it appears that only a small subset of this population is prone to recurrent cirrhosis and liver-related mortality, reduction in the risk factors associated with histologic recurrence may concomitantly aid in reducing the more common cardiovascular and infectious complications that account for a high proportion of mortality in the post-LT NASH population.

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Merola et al. Table 1. Summary of main risk factors for development of posttransplant non-alcoholic steatohepatitis (NASH) Risk factors for development of NASH post-transplant Metabolic factors

Immunosuppression Donor factors

Obesity Hyperlipidemia Hyperglycemia Corticosteroids Calcineurin inhibitors Graft steatosis Graft genetics

NAFLD in 39% within five yr following transplant (27). Recurrence in this study was related to pretransplant obesity, post-transplant BMI, and postLT triglyceride levels as well as use of prednisone at six months. Recurrent NAFLD is closely related to a high frequency of coronary artery disease and infection-associated mortality, although current data demonstrate that overall five-yr survival in patients transplanted for NASH is not adversely affected by the presence of recurrent NAFLD (27). Immunosuppression

Risk factors

Identified factors for the development of post-LT NASH encompass three broad categories, as shown in Table 1. The principal risk appears to be the ongoing metabolic derangements in the host such as hyperglycemia, hyperlipidemia, and obesity (24–27). Secondly, these risks are exacerbated by the side effects of immunosuppressive agents used after LT (28–30). Finally, graft steatosis at implantation has been shown to influence both the occurrence and progression of NAFLD in LT patients (31–34). Although no prospective evidence is available at present, retrospective evidence strongly supports that treatment of these identified highrisk characteristics may provide a significant mortality benefit in the post-LT NASH population (35). Furthermore, these risk factors associated with the development of post-transplant NASH have been closely correlated to increased utilization of healthcare resources, the development of cardiac and cerebrovascular events, and patient mortality (36). In an era of limited organ availability, early identification of these risk factors is critical in patient selection for transplantation, perioperative optimization, and post-LT treatment and screening, although at present, there is a lack of evidence regarding whether treating particular risk factors in the preoperative and postoperative period alters long-term outcomes. Host metabolic factors

NAFLD is noted as the hepatic manifestation of the MS. Ninety percent of patients with NAFLD possess one component of MS, and nearly 60% of post-transplant patients meet criteria for MS, a rate near double that of the general population (24, 25). The presence of post-transplant MS has been closely correlated to recurrent NAFLD, along with high insulin requirements (26). A study by Dureja et al. examined post-LT liver biopsies in 88 patients with NASH and found recurrent

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Immunosuppressive medications play a significant role in exacerbating metabolic sequelae in the NASH population. Corticosteroids decrease insulin production and peripheral glucose absorption as well as increase hepatic glucose production, promoting post-transplant diabetes (28). Calcineurin inhibitors, including cyclosporine and tacrolimus, have been shown to be diabetogenic (29). These agents have known adverse effects of HTN and hypercholesterolemia, promoting hepatic steatosis. A recent study examining immunosuppression in the NASH population post-LT by Houlihan et al. demonstrated that this population is more susceptible to renal dysfunction (30). Future investigations regarding renal-sparing regimens and their effect on long-term outcomes in this population are needed. Donor factors

Graft genetics may play an important role in promoting NAFLD recurrence after LT. A recent study by Durmortier et al. demonstrated that the prevalence of graft steatosis at implantation was significantly greater among post-LT patients who developed NAFLD compared to those without post-LT NAFLD (31). Other recent studies have confirmed that donor graft steatosis poses a threefold risk to developing post-LT NAFLD (32). Genetic alleles affecting intrahepatic triglyceride content in both the graft and recipient have been shown to confer susceptibility for the risk of fibrosis and steatosis. One such widely studied allele includes PNPLA3 rs738409, for which the donor genotype was an important predictor of recurrent hepatitis C virus (HCV) fibrosis, while the recipient genotype has been demonstrated to have an increased risk of graft steatosis (33, 34). Other donor polymorphisms, involved in innate immunity, such as TLR4, have been identified as important factors in affecting the risk of late graft failure (37). These findings suggest that the interactions between donor and recipient genetics may have a

NAFLD following liver transplant profound effect on disease recurrence and graft survival. Prognosis

Among patients transplanted for NASH cirrhosis, a distinct subgroup of patients with NASH have been identified to be particularly prone to early mortality, even in the presence of low MELD scores. Poor prognostic predictors that characterize this high-risk cohort include age ≥60 yr, BMI ≥30, diabetes, and HTN, for which patients with these risk factors had a mortality rate of 50% within one yr as compared to a 85–90% one yr survival on patients without these characteristics and similar MELD scores (11). These high-risk features have been validated in other cohorts to portend significantly higher postoperative complication rates and overall worse survival within the NASH population (38, 39). Therefore, significant emphasis should be imposed on patient selection and minimizing early mortality in this cohort. At the present time, however, it remains unclear whether weight loss prior to LT, tight glycemic control, or blood pressure control can improve post-transplant survival in this subgroup of patients with NASH. Unlike other indications for LT, mortality in patients with NASH is most frequently attributable to early cardiovascular complications and sepsis, with liver-related complications associated with only a small fraction of deaths (40). The increased incidence of these complications is largely attributed to secondary illnesses associated with MS, such as renal impairment, HTN, and diabetes (40, 41). The impact of lifestyle, pharmacologic intervention on reducing these comorbidies in the post-transplant setting has not been investigated to date. However, overall post-transplant one-yr, three-yr, and five-yr survival among the NASH population is comparable to other common indications for LT including alcoholic liver disease patients, primary biliary cirrhosis, primary sclerosing cholangitis, cryptogenic cirrhosis, and HCV (1, 10, 42, 43). There are conflicting data regarding survival of patients with HCC and NASH. Some studies have been shown this population to have a better prognosis than HCV and HCC, despite their lower likelihood of getting transplanted, while others have demonstrated a significantly higher HCC-related mortality in the NASH population (40, 44, 45). Further investigation is needed with long-term follow-up beyond five yr to determine the prognosis of HCC in patients with NASH. While recurrent evidence of hepatic steatosis is observed in roughly 30–40% of patients within

two yr of LT, advanced NASH-induced fibrosis and cirrhosis occurs less frequently. A large study performed by Durmotier et al. evaluated 599 patients over a 10-yr period following LT for NASH, and noted hepatic steatosis in 31% of patients and recurrent cirrhosis in 2.3% of recipients (31). Similar results were noted in a study by Yalamanchili et al. that examined post-LT biopsies at set time-points in patients with NASH and cryptogenic cirrhosis and noted histologic recurrence of fatty liver and NASH in 31% and 4% of patients, respectively, over a five-yr follow-up period (46). Recurrent NASH itself may be one among many manifestations of host metabolic derangements that ultimately foreshadows cardiovascular morbidity. The follow-up period on many of these studies is limited, and the effects of recurrent NASH beyond five yr following LT have not been investigated. Therefore, it is unknown whether the effects of cardiovascular morbidities lead to an increased mortality in recurrent patients with NAFLD compared to those without recurrence beyond five yr after LT. Proposed treatments

A variety of interventions have been proposed for the treatment of NAFLD prior to transplantation (Table 2). The cornerstone for the prevention and management of NAFLD after LT is the minimization of the MS through combination of lifestyle changes and pharmacologic therapy (47). To date, however, there have been no published drug trials specifically targeting treatment of post-transplant NAFLD. A number of pharmacologic and surgical treatments have recently been proposed to reduce risk factors for obesity and the MS in transplant patients. Lifestyle modification

Exercise, weight loss, and dietary modification have been demonstrated to achieve significant improvements in patients with NASH. In a study by Promrat et al., 31 patients were randomized to an intensive lifestyle modification using a combination of diet, exercise, and behavioral counseling and shown to have a significant improvement in liver histology (48). A weight loss of >10% has been shown to induce improvements in fibrosis and histologic features of portal inflammation (49). The effects of lifestyle intervention are not dependent on weight loss alone however, as NASH patients with moderate- and low-intensity exercise regimens have demonstrated improvements in hepatic transaminases, in the absence of significant

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NAFLD following liver transplant References 1. CHARLTON MR, BURNS JM, PEDERSEN RA, WATT KD, HEIMBACH JK, DIERKHISING RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011: 141: 1249. 2. LUDWIG J, VIGGIANO TR, MCGILL DB, OH BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980: 55: 434. 3. WONG RJ, AGUILAR M, CHEUNG R et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015: 148: 547. 4. ANGULO P. Nonalcoholic fatty liver disease. N Engl J Med 2002: 346: 1221. 5. RAFIQ N, BAI C, FANG Y et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroentrol Hepatol 2009: 7: 234. 6. BUGIANESI E, LEONE N, VANNI E et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002: 123: 134. 7. BIANCHI G, MARCHESINI R, MARZOCHI R, PINNA AD, ZOLI M. Metabolic syndrome in liver transplantation: relation to etiology and immunosuppression. Liver Transpl 2008: 14: 1648. 8. FRACANZANI AL, BURDICK L, RASELLI S et al. Carotid artery intima-media thickness in nonalcoholic fatty liver disease. Am J Med 2008: 121: 72. 9. CHARLTON M, KASPAROVA P, WESTON S et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl 2001: 7: 608. 10. CONTOS MJ, CALES W, STERING RK et al. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl 2001: 7: 363. 11. MALIK SM, DEVERA MR, FONTES P, SHAIKH O, AHMAD J. Outcome after liver transplantation for NASH cirrhosis. Am J Transplant 2009: 9: 782. 12. BHAGAT V, MINDIKOGLU AL, NUDO CG, SCHIFF ER, TZAKIS A, REGEV A. Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease. Liver Transpl 2009: 15: 1814. 13. ROWE IA, WEBB K, GUNSON BK, MEHTA N, HAQUE S, NEUBERGER J. The impact of disease recurrence on graft survival following liver transplantation: a single centre experience. Transpl Int 2008: 21: 459. 14. TINIAKOS DG. Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis: histological diagnostic criteria and scoring systems. Eur J Gastroenterol Hepatol 2010: 22: 643. 15. STRAUB BK, SCHIRMACHER P. Pathology and biopsy assessment of non-alcoholic fatty liver disease. Dig Dis 2010: 28: 197. 16. PATIL DT, YERIAN LM. Evolution of nonalcoholic fatty liver disease recurrence after liver transplantation. Liver Transpl 2012: 18: 1147. 17. CHALASANI N, YOUNOSSI Z, LAVINE JE et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012: 55: 2005. 18. CALDWELL SH, CRESPO DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol 2004: 40: 578.

19. MATSUI O, KADOYA M, TAKAHASHI S et al. Focal sparing of segment IV in fatty livers shown by sonography and CT: correlation with aberrant gastric venous drainage. Am J Roentgenol 1995: 164: 1137. 20. SCHAFFNER F, POPER H. Capillarization of hepatic sinusoids. Gastroenterology 1963: 44: 239. 21. NOSADINI R, AVOGARO A, MOLLO F et al. Carbohydrate and lipid metabolism in cirrhosis. Evidence that hepatic uptake of gluconeogenic precursors and of free fatty acids depends on effective hepatic flow. J Clin Endocrinol Metab 1984: 58: 1125. 22. SODERBERG C, STAL P, ASKLING J et al. Decreased survival of subjects with elevated liver function tests during a 28year follow-up. Hepatology 2010: 51: 595. 23. KLEINER DE, BRUNT EM, VAN NATTA M et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005: 41: 1313. 24. SIDDIQUI MS, STERLING RK. Posttransplant metabolic syndrome. Int J Hepatol 2012: 2012: 891516. 25. LAISH I, BRAUN M, MOR E, SULKES J, HARIF Y, BEN ARI Z. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transpl 2011: 17: 15. 26. EL ATRACHE MM, ABOULJOUD MS, DIVINE G et al. Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome. Clin Transplant 2012: 26: E505. 27. DUREJA P, MELLINGER J, AGNI R et al. NAFLD recurrence in liver transplant recipients. Transplantation 2011: 91: 684. 28. SCHACKE H, DOCKE WD, ASADULLAH K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002: 96: 23. 29. OZBAY LA, SMIDT K, MORTENSEN DM, CARSTENS J, JORGENSEN KA, RUNGBY J. Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells. Br J Pharmacol 2011: 162: 136. 30. HOULIHAN DD, ARMSTRONG MJ, DAVIDOV Y et al. Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: time to reconsider immunosuppression regimens? Liver Transpl 2011: 17: 1292. 31. DUMORTIER J, GIOSTRA E, BELBOUAB S et al. Non-alcoholic fatty liver disease in liver transplant recipients: another story of “seed and soil.” Am J Gastroenterol 2010: 105: 613. 32. KIM H, LEE K, LEE KW et al. Histologically proven nonalcoholic fatty liver disease and clinically related factors in recipients after liver transplantation. Clin Transplant 2014: 28: 521. 33. FINKENSTEDT A, AUER C, GLODNY B et al. Patatin-like phospholipase domain-containing protein 3 rs738409-G in recipients of liver transplant is a risk factor for graft steatosis. Clin Gastroenterol Hepatol 2013: 11: 1667. 34. DUNN W, O’NEIL M, ZHOA J et al. Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C. Hepatology 2014: 59: 453. 35. NEWSOME PN, ALLISON ME, ANDREWS PA et al. Guidelines for liver transplantation for patients with non-alcoholic steatohepatitis. Gut 2012: 61: 484. 36. AGOPIAN VG, KALDAS FM, HONG JC et al. Liver transplantation for nonalcoholic steatohepatitis: the new epidemic. Ann Surg 2012: 256: 624. 37. OETTING WS, GUAN W, SCHLADT DP et al. Donor polymorphisms of toll-like receptor 4 associated with graft failure in liver transplant recipients. Liver Transpl 2012: 18: 1399.

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NAFLD following liver transplant present in patients not on cyclosporine-based therapy. ACE Inhibitors

Angiotensin receptor inhibition has been demonstrated to improve insulin sensitivity, reduce hepatic triglycerides, and decrease oxidative stress (58–60). A recent retrospective study demonstrated that angiotensin-converting enzyme (ACE) inhibitors use reduced risk of developing de novo NAFLD after liver transplantation (61). However, to date, no prospective data on use of ACE inhibitors in this population of patients are available. A preliminary study of 12 patients demonstrated that losaratan 50 mg daily can improve biochemical parameters, liver steatosis, and inflammation on biopsy (62). Furthermore, a larger study compared the efficacy of telmisartan 20 mg daily with valsartan 80 mg daily and demonstrated improvement in transaminase levels and NASH fibrosis scores in those treated with telmisartan (63). Despite success in these small studies, larger randomized controlled trials are needed to directly assess the effectiveness of ACE inhibitors and ARBs in the treatment of NAFLD. Pentoxifylline

Pentoxifylline has recently been evaluated as pharmacologic treatment option for NASH. With known effects on reducing blood viscosity and platelet aggregation, pentoxifylline has been thought to have hepatoprotective effects in increasing glutathione levels, reducing production of oxygen free radicals and, in consequence, mediating antifibrotic effects (64, 65). A meta-analysis including five randomized controlled trials concluded that pentoxifylline improves histological features including fibrosis and biochemical marks compared to placebo patients in patients with NASH (66). There have been no studies examining the use of pentoxifylline for NASH in the post-LT setting. Metformin

Metformin has been proposed as a treatment for NAFLD as early studies claimed a reduction in hepatocyte ballooning, improvement of insulin resistance, and prevention of complications related to diabetes reduction in the risk of HCC without resultant weight gain (67–69). In NAFLD patients, a Cochrane analysis demonstrated that metformin was associated with both a reduction and normalization of liver enzymes in the general population (70). Despite these promising claims, more recent

investigations have failed to replicate change in insulin sensitivity, liver transaminases, and liver histology with metformin use (71–73). Many experts feel that earlier studies were confounded by significant weight loss in patients with NASH for which beneficial effects were noted. At present, expert guidelines do not advocate for the use of metformin as treatment for liver disease in adults with NASH (17). Furthermore, guidelines for posttransplant patients caution the use of metformin as a first-line agent of choice due to concerns for worsening renal insufficiency and drug interactions with immunosuppressive regimens (74). Metformin use in the setting of renal insufficiency may rarely result in lactic acidosis and is perhaps the most common contraindication for its use in the posttransplant setting. Moreover, GI side effects of mycophenolate mofetil may be potentially exacerbated by metformin use. While no randomized studies have addressed the use of metformin in the LT population, many experts have advocated for its use in this population based on several studies that have demonstrated potential benefit and case reports that have favorably advocated its use despite the aforementioned risks. A recent case report by Kobayashi et al. noted successful glucose control when using metformin in combination with nateglinide daily after living-donor transplantation in diabetics (75). Moreover, the treatment of a pediatric patient with NASH recurrence with metformin six months after diagnosis successfully resulted in the resolution of elevated liver transaminases (76). Despite these reports, there is not at present sufficient data to advocate for the use of metformin in the posttransplant setting. Peroxisome proliferator-activated receptor (PPAR) agonists

Insulin sensitizers, most notably pioglitazone, have been tried in combination with caloric restriction as a possible treatment of NASH and have been shown to significantly improve liver histology and biochemical parameters (77). However, significant weight gain is associated with these therapies and has limited their use in this population (78). Longterm trials are needed to fully elucidate whether the histologic benefits outweigh potential cardiac and carcinogenic morbidities observed (79). Promising agents

A number of recent agents have been recently described for the treatment of NASH and are currently under investigation. Obeticholic acid is a bile

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acid derivative and a potent activator of the farnesoid X nuclear receptor shown to reduce liver adiposity and fibrosis in animal models by promoting insulin sensitivity and enhancing peripheral clearance of very low-density lipoprotein (VLDL) (80). Treatment with this agent has been recently shown to diminish progression and potentiate regression of fibrosis (80). Obeticholic acid is often used in combination with a statin as it has been shown to increase LDL levels when used alone (80). Remogliflozin etabonate is an inhibitor of SGLT2, an important sodium-glucose transport protein responsible for renal glucose reabsorption, initially identified as an effective treatment for diabetes mellitus. Recent post hoc analysis of the remogliflozin trials has demonstrated 30–40% reductions in hepatic transaminase levels after 12 wk of treatment and has proposed its use for the treatment of NASH (81). Liraglutide is a glucagon-like peptide1 analog currently in phase II trials for the treatment of NASH. Preliminary evidence has demonstrated significantly increased resolution of NASH on liver biopsy following a 48 wk course of once daily injection compared to placebo (82). These new therapies have not to date been examined in post-LT patients. Bariatric surgery

Obesity has been shown to have poor impact on transplant outcomes in patients with NASH and is closely associated with postoperative diabetes, heart disease, malignancy, and mortality. Early reports of bariatric surgery in patients with NASH noted significant hepatic decompensation, progressive steatosis and cholestasis, and development of encephalopathy following gastric bypass (83). More recent attempts have noted technical challenges secondary to adhesions and complications related to immunosuppressive therapies (84, 85). However, some recent reports have demonstrated promising results in establishing a role for bariatric surgery before and after transplantation (86–88). Heimbach et al. noted significant benefit to postLT diabetes mellitus, hepatic death, and graft loss when performing combined liver LT and sleeve gastrectomy in patients who failed an intensive weight loss program (89). In this study, seven patients who underwent combined LT with sleeve gastrectomy were compared to a control group of 37 LT patients who achieved weight loss with dietary and behavioral modifications alone. Patients who underwent sleeve gastrectomy were obese patients who had failed to achieve substantial weight loss with lifestyle modifications. Among the seven patients who underwent the combined proce-

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dure, there were no deaths or graft losses and no patients developed post-LT diabetes or liver steatosis after a mean follow-up of 17 months. One patient developed a gastric staple line leak and one had excess weight loss. Compared with the control population, the seven patients who underwent the combined procedure had fewer post-LT metabolic complications including diabetes, hepatic steatosis, and HTN (89). Although this report seems promising, studies with longer follow-up are needed to optimize patient selection for bariatric surgery in the NASH population. Future directions

In the post-LT setting, both immunosuppression and graft characteristics influence the safety and efficacy of pharmacologic agents used to treat NASH in the pre-transplant setting. While some treatments may be useful in the transplanted population, at present no randomized studies examining effective treatment strategies for the treatment of post-LT NASH have been performed. As recurrent NASH cirrhosis is a relatively small contributor to overall post-LT mortality, emphasis should be placed on reducing cardiovascular and infectious complications in patients with NASH. The rapidly growing population of post-LT NASH patients provides an opportunity to perform large, multicenter studies to help optimize preoperative selection and optimal immunosuppressive regimens and determine optimal lifestyle, pharmacologic, and surgical approaches targeted to reduce post-LT MS. Moreover, a multidisciplinary protocol approach, available to most transplant patients, which integrates expertise in cardiovascular medicine, endocrinology, surgery, nutrition, and behavioral psychology geared toward reducing identified risk factors, may provide the most effective management of transplanted patients with NASH. Conclusion

NASH is a challenging, multifactorial disease on track to become the most common indication for LT over the coming decade. While outcomes are comparable to LT performed for other complications, morbidity and mortality can be significantly improved by thorough perioperative risk stratification, optimizing metabolic risk factors and tailoring immunosuppressive regimens. While several promising pharmacologic and surgical approaches have been observed, long-term studies with clinical endpoints are desperately needed to improve care in this rapidly expanding patient population.

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